Abstract: Ras is an evolutionarily conserved signaling molecule that plays a central and critical role in cells of the immune system. We sought to better understand the intricacies and importance of Ras activation, signaling, and regulation in the function of CD4+ T cells. To this end, we investigated the mechanism(s) of Ras activation induced by stimulation of distinct receptors expressed on CD4+ T cells, the role of Ras pathway engagement in CD28-mediated costimulation of the T cell receptor complex, and the significance of Ras signal regulation in Th1/Th2 differentiation. Engagement of both the T cell receptor signaling complex and the IL-2 receptor signaling complex by their respective ligands induces robust Ras activation in CD4+ T cells. However, differences between these two receptors suggest that the mechanism of Ras activation employed by each of these receptors may be distinct. We have demonstrated that the mechanism of Ras activation induced by the T cell receptor complex differs from the mechanism employed by IL-2 receptor complex in terms of the activating RasGEF utilized. The precise molecular mechanisms controlling CD28-mediated costimulation of T cell activation remain enigmatic despite their clear potential as sites of therapeutic intervention. Although previous studies have suggested a role for Ras signaling in CD28-mediated costimulation, the ability of Ras pathway activation to mediate functional aspects of CD28 costimulation has never been demonstrated. We have shown that activation of the Ras signaling pathway can mimic the major functional consequences of CD28-costimulation, thus implicating a central role for Ras signaling in this process. Finally we have offered insight into a relatively sparse field of knowledge regarding the importance of signal duration on both proximal as well as distal events in the function of a T cell. We have shown that despite augmenting acute activation, forced maintenance of Ras signaling during the priming of CD4+ T cells impairs their forward differentiation into Th1/Th2 effector cells. Together these data have provided a valuable contribution to the field of T cell signaling as well as the study of Ras and represent an exciting foundation from which to launch further investigations into Ras signaling in T cells.