T cells undergo clonal expansion upon encountering cognate antigen in peripheral lymphoid tissues. They require signals through both the T cell receptor and the costimulatory receptor CD28 for this process to occur. In the absence of CD28 stimulation, T cell receptor signals are repressed by the ubiquitin ligase Cbl-b, which negatively regulates the activity of the downstream effectors PI3Kp85 and Vav1. CD28 signals overcome this repression, at least in part, by ubiquitinating and degrading Cbl-b itself. CD28 signals induce clustering of cell-surface receptors, cell division and optimal interleukin-2 production. The Cbl-b/CD28 regulatory axis has profound implications for pathological conditions ranging from autoimmunity to cancer.