SWAP-70-like adapter of T cells (SLAT) is a recently identified guanine nucleotide exchange factor (GEF) for Cdc42 and Rac1, which is highly expressed in both thymocytes and peripheral T cells. Here, we present and discuss findings resulting from biochemical and genetic analyses aimed at unveiling the role of SLAT in CD4+ T-cell development, activation, and T-helper (Th) cell differentiation. Slat(-/-) mice display a developmental defect at one of the earliest stages of thymocyte differentiation, the double negative 1 (DN1) stage, leading to decreased peripheral T-cell numbers. Slat(-/-) peripheral CD4+ T cells demonstrate impaired T-cell receptor/CD28-induced proliferation and IL-2 production. Moreover, SLAT positively regulates the development of Th1 and Th2 inflammatory responses by controlling Ca2+/NFAT signaling. SLAT is also a positive regulator of the recently emerging Th subset, i.e., Th17 cells, as evidenced by its critical role in Th17 cell-mediated central nervous system inflammation. Furthermore, TCR engagement induces SLAT translocation to the immunological synapse, a process mediated by its Lck-dependent phosphorylation, which thereafter facilitates the triggering of SLAT GEF activity towards Cdc42 and Rac1, leading to NFAT activation and Th1/Th2 differentiation. Future work will aim to dissect the interacting partners of SLAT and may thus shed light on the poorly understood events that coordinate and link actin cytoskeleton reorganization to Ca2+ signaling and gene transcription in T cells.