The past year has seen remarkable advances in our understanding of how members of the Ras superfamily of GTPases are activated. Not only have new guanine-nucleotide exchange factors (GEFs) that activate these GTPases been identified, but in some cases, the mechanisms by which GEFs are connected to events at the cell surface have also been described. We have also come to appreciate the possibilities that GEFs may be multifunctional and that they may contribute to tissue-specific regulation of their cognate GTPase.