Almost a decade ago, the small GTPase Ras was shown to be activated in response to antigen receptor triggering in T cells. Since then, Ras has been further characterized as a central molecule for the regulation of signal transduction pathways in lymphocytes. However, over the last couple of years, its exclusive role in lymphocyte biology has been challenged by the emergence of its relatives of the Rho family. Today it is well established that Rho GTPases act as unique molecular switches at several critical checkpoints in lymphocyte development and function. Additionally, a new and critical concept in GTPase signaling has taken shape over the last couple of years in that small GTPases are able to regulate quite diverse cellular processes in the immune response by linking to multiple biochemical effector pathways.