The acquisition of transplantation tolerance is an active, highly regulated, and multistep process. In this review, we critically examine the validity and limits of the Th1/Th2 paradigm during the period of tolerance induction. We emphasize that host response to major histocompatibility complex–mismatched allografts encompasses an unusually large population of T-cell clones and involves both direct and indirect recognition of foreign major histocompatibility complex antigen. Thus, control of robust expansion of alloaggressive T-cell clones and proliferation is a critical initial step in the acquisition of transplantation tolerance.