Mar.Drugs 2014,12 1071 observed that a sponge lays alone in the habitat,and around it there is a clean area,most probably,its metabolites inhibit the growth of competing organisms [50].Unfortunately,these sampling facilities are very expensive and only a small number of laboratories have access to them,a drawback that is difficult to overcome,especially if we think that the majority of biological diversity is located in underdeveloped countries from the tropical and subtropical regions [51].This is just one of the reasons why international collaboration is so important in this research field.However,the access to biodiversity on natural resources is now under the host of the Convention on Biological Diversity (CBD).Unfortunately.the different levels of Nagova protocol implementation (which clarifies the scope of the CBD)in different regions,and the increasing difficulties to work under a still unclear regulatory framework on biodiversity access may push current industries out of the NP arena The lack of taxonomic knowledge for marine species,and the still large number of unidentified species and strains,is alsoa major blockage faced by marine natural products programs.The selection for pharmacological purposes.of macro or microorganisms.either terrestrial or marine.must be grounded on a correct taxonomic identification and classification.An incorrect classification of a species may compromise an entire drug discovery project,not only because it is impossible to reproduce the isolation in the event of a bioactive extract and/or metabolite.but also because it can mislead the dereplication process-the process by which the bioactives are identified.Approaches to classification of marine macroorganisms (algae and invertebrates)and microorganisms(fungi and bacteria)are quite different.For the majority of marine macroorganisms taxonomic knowledge is still insufficient to enable unambiguous species classification [52].Macroinvertebrates are especially challenging.not only due the fact that there are still many undescribed species.but also because many related species must be distinguished based on subtle morphological characteristics [531 Following the process of target identification and validation,the next step of a drug discovery process is the development of the screening assays.A variety of screening paradigms exist to identify hit molecules [54]being HTS the most widely used in the case of NP.The success key to apply HTS methodology to NP is constructing high quality libraries.Researchers at Pfizer proposed that the output from HTS is dependent on the interrelationships between the quality of the compound library. the target and the screening process [55].Ideally,the library itself should be composed by crud extracts.simplified extract fractions and pure compounds for a well-balanced natural product discovery program [56].Crude extract libraries are easier and cheaper to construct,have moderate overall size and a high degree of diversity,but have major disadvantages when compared with pure compounds libraries.Crude extracts are complex mixtures of several compounds that may have synergistic interaction.a fact that accounts for the disappearance of the bioactivity in purified fractions and,ultimately,in final pure compounds [57].On the other hand,false negative readouts may also be obtained.either because an active metabolite is present in a small percentage in the crude extract.or because of the interference of compounds such as tannins [56]that bind to other metabolites masking its activity.Due to these reasons.in a recent past this approach was discouraged in drug discovery programs [56].Screening pre-fractionated libraries is an effective strategy to avoid these problems [3]. Depending on the method used for pre-fractionation and on the number of compounds in the original crude extract,the resulting fractions can vary widely in complexity from a mixture of multiple compounds to a single major compound of%purity.Pre-fractionation can eliminate several undesired compounds and facilitate hit identification.Mar. Drugs 2014, 12 1071 observed that a sponge lays alone in the habitat, and around it there is a clean area, most probably, its metabolites inhibit the growth of competing organisms [50]. Unfortunately, these sampling facilities are very expensive and only a small number of laboratories have access to them, a drawback that is difficult to overcome, especially if we think that the majority of biological diversity is located in underdeveloped countries from the tropical and subtropical regions [51]. This is just one of the reasons why international collaboration is so important in this research field. However, the access to biodiversity on natural resources is now under the host of the Convention on Biological Diversity (CBD). Unfortunately, the different levels of Nagoya protocol implementation (which clarifies the scope of the CBD) in different regions, and the increasing difficulties to work under a still unclear regulatory framework on biodiversity access may push current industries out of the NP arena. The lack of taxonomic knowledge for marine species, and the still large number of unidentified species and strains, is also a major blockage faced by marine natural products programs. The selection, for pharmacological purposes, of macro or microorganisms, either terrestrial or marine, must be grounded on a correct taxonomic identification and classification. An incorrect classification of a species may compromise an entire drug discovery project, not only because it is impossible to reproduce the isolation in the event of a bioactive extract and/or metabolite, but also because it can mislead the dereplication process—the process by which the bioactives are identified. Approaches to classification of marine macroorganisms (algae and invertebrates) and microorganisms (fungi and bacteria) are quite different. For the majority of marine macroorganisms taxonomic knowledge is still insufficient to enable unambiguous species classification [52]. Macroinvertebrates are especially challenging, not only due the fact that there are still many undescribed species, but also because many related species must be distinguished based on subtle morphological characteristics [53]. Following the process of target identification and validation, the next step of a drug discovery process is the development of the screening assays. A variety of screening paradigms exist to identify hit molecules [54] being HTS the most widely used in the case of NP. The success key to apply HTS methodology to NP is constructing high quality libraries. Researchers at Pfizer proposed that the output from HTS is dependent on the interrelationships between the quality of the compound library, the target and the screening process [55]. Ideally, the library itself should be composed by crude extracts, simplified extract fractions and pure compounds for a well-balanced natural product discovery program [56]. Crude extract libraries are easier and cheaper to construct, have moderate overall size and a high degree of diversity, but have major disadvantages when compared with pure compounds libraries. Crude extracts are complex mixtures of several compounds that may have synergistic interaction, a fact that accounts for the disappearance of the bioactivity in purified fractions and, ultimately, in final pure compounds [57]. On the other hand, false negative readouts may also be obtained, either because an active metabolite is present in a small percentage in the crude extract, or because of the interference of compounds such as tannins [56] that bind to other metabolites masking its activity. Due to these reasons, in a recent past this approach was discouraged in drug discovery programs [56]. Screening pre-fractionated libraries is an effective strategy to avoid these problems [3]. Depending on the method used for pre-fractionation and on the number of compounds in the original crude extract, the resulting fractions can vary widely in complexity from a mixture of multiple compounds to a single major compound of >90% purity. Pre-fractionation can eliminate several undesired compounds and facilitate hit identification