In vitro and in silico studies have suggested that strong Ras activation in T cells requires a feedback loop involving both RasGRP and SOS1 while weak or transient Ras activation can be achieved by RasGRP1 alone, without SOS. In thymocytes, this has led to models in which weak ligands mediate positive selection via RasGRP1- induced Ras signaling in the Golgi membrane, while strong ligands induce negative selection via combined RasGRP/SOS1- mediated Ras activation at the plasma membrane. The nature of Ras signaling in peripheral T cells is equally complex. The role of SOS1 in Ras-mediated ERK activation in peripheral is controversial due to contradicting studies in which targeted SOS1 deletion has had both positive and negative effects. In addition to canonical pathways in which Ras activation via RasGRP1 and Sos1 is dependent on TCR-induced LAT phosphorylation, studies in mice harboring a mutation in the PLCc binding site of LAT have demonstrated that Ras is also activated via a non-canonical, RasGRP-dependent pathway that involves Lck-PKC-h interactions but that is LAT and PLC-cindependent. Lck-PKC-h interactions have previously been reported to occur in the context CD28 co-stimulation which data from our laboratory has suggested may be mediated by Ras signaling. Finally, TCR-induced ERK phosphorylation also has been reported to be induced via a Bam32–PLC-c1-PAK1 medicated-mechanism that is independent of Ras. Previous work from our laboratory has demonstrated that active Ras signaling can functionally bypass the requirements for CD28 co-stimulation of the T cell receptor during acute activation. Additionally, we have observed that anergic CD4+ T cells show MK-4827 blunted TCR-induced Ras activation, and that introduction of active Ras into anergic Th1 cells could bypass proximal signaling defects and restore IL-2 production. These observations raised the question of whether introduction of active Ras into naı¨ve T cells could generate a phenotype that was hyperresponsive and anergy-resistant. Engineering of such a phenotype could have practical utility in maintaining T cell function in the setting of anti-tumor immunity or chronic infections in which T cell function becomes blunted over time. A critical function of CD4+ T cells is their ability to differentiate from naı¨ve to effector cells of either the Th1 or Th2 lineage, which is a highly regulated, complex process that is essential to the proper execution and shaping of the immune response. These differentiation events involve defined phenotypic changes that result in cells capable of producing lineage-specific effector cytokines. These changes include the upregulation of receptors for polarizing cytokines, productive signaling through these receptors to activate lineage-determining transcription factors STAT4 and STAT6, upregulated expression of lineagespecific transcription factors T-bet and GATA-3, and finally, the remodeling of genetic loci of the effector cytokines specific to each lineage to allow cytokine transcription, protein synthesis and secretion.