This chapter describes the principles of T cell responses and how such responses are targeted to promote transplant survival. T cells must be activated before becoming effector cells. T cell activation begins with engagement of the TCR by antigens. Stimulation of T cells through both the TCR and costimulatory signals results in tyrosine phosphorylation mediated by activation of the lipid kinase, phosphatidylinositol 3'-hydroxyl kinase (PI3K). Following activation, T cells proliferate rapidly and develop into effector T cells with cytotoxic and other functions. In a primary immune response, T lymphocytes are activated, expand exponentially, and differentiate to effectors. The chapter describes mechanisms involved in contraction, memory T cell generation, and maintenance. Pre-existing alloreactive memory T cells present an important obstacle to successful transplantation. The diversity of T cells and their complex biology provides a great challenge to clinical transplantation in selecting therapeutic targets.