This review focuses on the emerging body of literature suggesting a critical role for CD40/CD154 interactions in antigen-presenting cell (APC) activation, CD4+ and CD8+ T cell priming, and effector T cell maturation. In this context effective antigen presentation involves not only T cell expansion and long-term survival but also the ability of the APC to guide the T cell response toward the Th1 (interferon-gamma producing) or the Th2 (interleukin-4 producing) phenotype. We suggest a model to explain why CD40/CD154 interactions are critical for some helper and cytotoxic T cell responses, whereas others occur independently of this receptor/ligand pair. In addition, we will discuss the potential role for CD40/CD154 interactions in effector T cell maturation and cytokine production.