It is widely accepted that Th1 helper T lymphocytes (HTL)* initiate allograft rejection by promoting the development of alloantigen-specific cytotoxic T lymphocytes (CTL) and delayed-type hypersensitivity (DTH) responses. Since Th2 HTL are antagonistic to Th1 development and function, a popular hypothesis states that preferential induction of allograft-specific Th2 would down-regulate Th1-driven rejection responses, thereby promoting allograft acceptance. This possibility would have direct application to clinical transplantation, in that preferential induction of Th2 may be accomplished by cytokine manipulation both in vitro and in vivo. While attractive, this hypothesis has not been rigorously tested, and the majority of evidence that supports or refutes its premises is associative in nature. In this Overview, studies that associate allograft-specific Th2 with both beneficial and deleterious responses are summarized, and recent studies aimed at preferential induction of allograft-specific Th2 through cytokine manipulation are discussed.