During brain development, attractive and repulsive signals establish functional connections within the brain by guiding the growth of axons. The genetic and transcriptional regulation of axonal guidance is poorly understood but, on p. 5527,Marion et al. report that, in the developing mouse brain, the transcription factors SIM1 and SIM2 are required for the correct targeting of mammillary body axons, part of the neuronal circuitry involved in spatial learning. The authors show, for example, that, in mouse embryos that lack both copies of Sim1 and one or two copies of Sim2, mammillary body neurons form but fail to lay down normal axonal projections. Overall, the researchers conclude that Sim1 and Sim2 play similar roles in vivo, and suggest that they should be added to the growing list of transcription factors that regulate the expression of molecules that control axonal morphology and connectivity.