The most obvious conclusion from this survey is that neuronal signaling proteins, for the most part, have been highly conserved throughout evolution. Despite the dramatic differences in complexity and organization of nervous systems and behavioral outputs in worms, flies, and mammals, the key proteins, and presumably the functional mechanisms they govern, are remarkably similar. Apparently, the basic framework for neuronal signaling and synaptic organization was completed early in metazoan evolution, and evolution of much more complicated nervous systems did not entail extensive alteration of this framework. Thus, genomic analysis fully confirms the belief that one can obtain fundamental neurobiological insights from studies of simple model organisms.Still, at this point, it is easier to catalog the information obtained from sequence analysis than to decipher all the functional implications. It is not in any way apparent, for example, why C. elegans, with only 302 neurons, encodes more than 90 K+ channels. Drosophila with a nominally more complex nervous system and behavioral repertoire has a set of only about 30 K+ channel genes. Indeed, most ion channel gene families contain more members in worms than flies. Apparently, increased behavioral complexity does not require an increase in molecular complexity but may depend instead on increases in the number of neurons and the complexity of the wiring diagram. Although somewhat counterintuitive, a greater number of ion channels may be required in worms than flies to provide its simple nervous system with the potential for more extensive signaling capabilities than would otherwise be possible.With the identification in this analysis of new channel subfamilies, it is likely that all the major classes of channel pore-forming subunits have now been described and the complete set of evolutionarily conserved ion channels has been defined. Although this would not have been obvious a priori, there is a striking difference between ion channel pore-forming subunits and auxiliary subunits with respect to evolutionary conservation. With the exception of Ca2+ channels, very few of the accessory subunits identified in mammals have homologous counterparts in worms or flies. The acquisition of novel ion channel subunits that modify the biophysical properties of pore-forming subunits may represent one way of adding additional functional complexity to the basic set of channels.It remains an open question whether the more complex nervous systems of vertebrates, particularly mammals, employ any signaling mechanisms that are fundamentally different from those in invertebrates. If so, the strong conservation of the basic set of signaling proteins argues that these mechanisms either depend on an unknown set of proteins or involve the same components that can be incorporated into novel molecular and cellular networks that generate unique functions and outputs.From the perspective of the genome, it seems safe to predict that elucidation of the fundamental molecular mechanisms of neuronal signaling applicable to all organisms will continue to derive enormous benefit from invertebrate model systems. With future emphasis on understanding the distinctive in vivo functions of the array of proteins now defined only by sequence, the availability of forward and reverse genetic techniques in worms and flies will continue to be of critical importance. The identification of the entire set of ion channels and neuronal signaling proteins opens up a new era in which neurobiologists can work back from the complete gene set toward an understanding of how they function to produce behavior.‡To whom correspondence should be addressed (e-mail: troy@mit.edu).