The NGF family of neurotrophins has a crucial role in regulating neuron numbers during vertebrate development. Six years ago the prediction was made that invertebrates with simple nervous systems, such as Caenorhabditis elegans, would lack neurotrophins. Surprisingly, it now appears that not only C. elegans but also Drosophila melanogaster, lack homologs of the neurotrophins or their trk receptors. Furthermore, functional studies indicate that control of neuronal numbers in Drosophila is primarily dependent on steroids. By contrast, a recognizable trk homolog exists in molluscs, a phylum that includes species with the most complex nervous systems in the invertebrate kingdom. This suggests that neurotrophic signaling mechanisms might be one of the prerequisites for evolution of complex nervous systems. Expansion of the genome projects to other invertebrates, such as molluscs and coelenterates, should provide new insights on the molecular correlates of building complex brains.