T‐cell proliferation and function depends on signals from the antigen‐receptor complex (TCR/CD3) and by various co‐receptors such as CD28 and CTLA‐4. The balance of positive and negative signals determines the outcome of the T‐cell response to foreign and self‐antigen. CD28 is a prominent co‐receptor in naiÅNve and memory T‐cell responses, and its blockade has been exploited clinically to dampen T‐cell responses to self‐antigen. Current evidence shows that CD28 both potentiates TCR signaling and engages a unique array of mediators (PI 3K, Grb2, FLNa) in the regulation of aspects of T‐cell signaling including the transcription factor NFκb. In this mini‐review, we provide an up‐to‐date over‐view of our understanding of the signaling mechanisms that underlie CD28 function and its potential application to the modulation of reactivity to autoimmunity.