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 naïve and memory T-cell responses. 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 (PI3K, Grb2, FLNa) in the regulation of aspects of T-cell signaling including the transcription factor NFkB. In this mini-review, we provide an up-to-date overview of our understanding of the signaling mechanisms that underlie CD28 function and its potential application to the modulation of reactivity to autoimmunity.