Neurotoxins belonging to the group of saxitoxin (STX) and tetrodotoxin (TTX) analogs are guanidinium alkaloids that share a common high affinity and ion flux blockage capacity for voltage-gated sodium ion channels (Nav. Members of the STX group, also known as paralytic shellfish toxins (PST), are produced among three genera of marine dinoflagellate and several genera of phylogenetically distant and primarily freshwater filamentous cyanobacteria. The origin of the biosynthetic genes in dinoflagellates remains controversial and may represent single or multiple horizontal gene transfer (HGT) events from progenitor eubacteria and/or cyanobacteria. The TTXs occur primarily among marine puffer fish and a host of terrestrial amphibians. The biosynthetic pathway has not been completely elucidated and the origin of tetrodotoxicity,including the syndrome puffer fish poisoning (PFP) in human seafood consumers,remains somewhat enigmatic. Although symbiotic bacteria are most often invoked as the source of TTX in macrofauna, endogenous biosynthesis independent of bacteria cannot be excluded. Integration of knowledge on the biogenic origins, linked to heterogeneity of the biogeographical and phylogenetic distribution of these respective toxin groups, provides the basis for rational inferences and reasonable speculation about the functional role in aquatic and terrestrial ecosystems. Recent identification of the biosynthetic genes for STX analogs in both cyanobacteria and dinoflagellates has yielded insights into biosynthetic mechanisms of toxin heterogeneity among strains and the evolutionary origins of their respective elements of the toxin gene clusters. Although it is not fully understood how or why these molecules are produced in nature, development of improved detection methods will make possible the discovery of new sources and analogs. Once genetic mechanisms for toxin biosynthesis are fully incorporated with modeling of receptor binding interactions and the structural–functional affinities of the ion channels, this will facilitate further biotechnological exploitation of these exquisite bioactive compounds and point the way toward future development of pharmaceuticals and therapeutic applications.