Transcription regulatory networks governing the genesis, maturation and maintenance of vertebrate brain serotonin (5-HT) neurons determine the level of serotonergic gene expression and signaling throughout an animal's lifespan. Recent studies suggest that alterations in these networks can cause behavioral and physiological pathogenesis in mice. Here, we synthesize findings from vertebrate loss-of-function and gain-of-function studies to build a new model of the transcriptional regulatory networks that specify 5-HT neurons during fetal life, integrate them into CNS circuitry in early postnatal life and maintain them in adulthood. We then describe findings from animal and human genetic studies that support possible alterations in the activity of serotonergic regulatory networks in the etiology of mental illness. We conclude with a discussion of the potential utility of our model, as an experimentally well-defined molecular pathway, to predict and interpret the biological effect of genetic variation that may be discovered in the orthologous human network.