CD4+ T-cell-mediated autoimmune diseases are initiated and maintained by the presentation of self-antigen by antigen-presenting cells (APCs) to self-reactive CD4+ T-cells. According to the two-signal hypothesis, activation of a naïve antigen-specific CD4+ T-cell requires stimulation of both the T-cell antigen receptor (signal 1) and costimulatory molecules such as CD28 (signal 2). To date, the majority of therapies for autoimmune diseases approved by the Food and Drug Administration primarily focus on the global inhibition of immune inflammatory activity. The goal of ongoing research in this field is to develop antigen-specific treatments which block the deleterious effects of self-reactive immune cell function while maintaining the ability of the immune system to clear nonself antigens. To this end, the signaling pathways involved in the induction of CD4+ T-cell anergy, as apposed to activation, are a topic of intense interest. This chapter discusses components of the CD4+ T-cell activation pathway that may serve as therapeutic targets for the treatment of autoimmune disease.