The concept of identifiable bioactive agents from the marine environment goes back to the middle part of the twentieth century, though there were sporadic reports of medicinal properties of algae and other marine organisms from Japanese and Traditional Chinese Medicine sources, but no definitive identification of the compound(s) was/were made. This chapter discusses the problems associated with determining the structures of bioactive materials isolated from sponges to show how earlier reported structures were significantly revised before any potential agent could be studied. Then, a discussion of the initial chemical studies led to a revision of the then “Current Dogma” as to the bioactivity of nucleosides, which led to very potent antivirals and antitumor agents now known to be from marine invertebrate-associated microbes. Then there are examples and discussion of the highly potent (mainly antitumor) agents that, though initially isolated from sponges, are now known to be from associated microbes (mostly yet uncultivated) to agents that are now made totally by synthesis and are probably from dinoflagellate associates of the “nominally producing sponge.” These agents also include RIPPS, which are covered in detail in Chap. 7 . Included is a short discussion of the currently approved agents related to the original bioactive compounds associated with the “sponge host,” most chemically modified to make them amenable to use as human drugs.