NPAS3 is a member of the basic helix-loop-helix PAS domain class of transcription factors expressed in the brain. Evidence from a human chromosomal rearrangement and a mouse knock-out strain suggest that it may play a part in the aetiology of psychiatric illness. In this review, we describe evolutionary constraints on the NPAS3 gene, relevant functional studies from a related gene and the behavioural and hippocampal neurogenesis deficit observed in the mutant mouse. In addition, we speculate on the physiological regulation of NPAS3 and whether NPAS3 gene variation contributes to psychiatric illness at the population level.