Small GTP-hydrolyzing enzymes (GTPases) of the RhoA family play manifold roles in cell biology and are regulated by upstream guanine nucleotide exchange factors (GEFs). Herein, we focus on the GEFs of the Vav subfamily. Vav1 was originally described as a proto-oncogene of the hematopoietic lineage. The GEFs Vav2 and Vav3 are more broadly expressed in various tissues. In particular, the GEF Vav3 may play important roles in the developing nervous system during the differentiation of neural stem cells into the major lineages, namely neurons, oligodendrocytes and astrocytes. We discuss its putative regulatory roles for progenitor differentiation in the developing retina, polarization of neurons and formation of synapses, migration of oligodendrocyte progenitors and establishment of myelin sheaths. We propose that Vav3 mediates the response of various neural cell types to environmental cues.