The activation of resting T cells is crucial to most immune processes. Recognition of foreign antigen by T-cell receptors has to be correctly translated into signal transduction events necessary for the induction of an effective immune response. In this review, we discuss the essential signals, molecules, and processes necessary to achieve full T-cell activation. In addition to describing these key biological events, we also discuss how T-cell receptor signaling may be harnessed to yield new therapeutic targets for a next generation of anti-cancer drugs.