Effective immune responses require the appropriate activation and differentiation of peripheral CD4⁺ T cells. These processes need to be followed by the timely elimination of the responding T cells in order to restore T cell homeostasis. Defects in the appropriate regulation of T cell activation, expansion, and survival underlie the pathogenesis of many autoimmune disorders including SLE. The molecular machinery employed by T cells to properly control these processes and prevent the onset of autoimmunity has not been fully elucidated. Rho GTPases (which include the Rac, Cdc42, and Rho subfamilies) are molecular switches that control a wide range of cellular processes. Their fundamental role in biology is due to their ability to regulate both cytoskeletal dynamics and a large number of signal transduction pathways. Activation of Rho GTPases is now recognized as a key event in the coordination of immune responses and, particularly, in the activation of T cells. In this review, we will first provide an overview of the role of Rho GTPase-mediated pathways in mature CD4⁺ T cells and then we will discuss recent studies, which suggest that deregulation of these pathways may play a role in the pathogenesis of SLE.