Left-right asymmetry is a conserved, but poorly understood, feature of animal nervous systems. Now, Robert Horvitz and colleagues reveal how a neuronal bilateral asymmetry is established in C. elegans (p. 4017). In C. elegans, the left-right asymmetric ABaraap cell lineage generates the single unpaired MI neuron and the e3D epithelial cell on the right and left sides, respectively, of the animal. The researchers show that the proneural bHLH genes ngn-1 and hlh-2, and the Otx homeodomain gene ceh-36 specify the MI neuron and establish this asymmetry – the determination of which occurs in the precursor cells for the left and right branches of the ABaraap lineage. Importantly, this initially cryptic asymmetry triggers activation on the right side only of a transcriptional cascade that then acts through multiple rounds of cell division, with CEH-36 functioning in the MI-grandmother cell, but not in the e3D-grandmother cell, to induce expression of NGH-1/HLH-2 in the MI-mother cell. Given their results, the researchers suggest that an evolutionarily conserved Otx/bHLH pathway establishes nervous system bilateral asymmetry in C. elegans and in other animals.