T cell-directed therapies have become mainstays in the management of various autoimmune diseases and organ transplantation. The understanding of T cell biology has expanded greatly since the development of most agents currently in use. Here we discuss important recent discoveries pertaining to T helper cell differentiation, lineage commitment, and function. Within this context, we examine existing T cell-directed therapies, including new agents being evaluated in clinical and preclinical studies. We also use recent findings to speculate on novel targets.