JAK3, a member of the Janus kinase family, has a crucial role in T-cell development and the homeostasis of the immune system because of its association with the common gamma chain (gammac) of cytokine receptors. Disruption of either JAK3 or gammac expression results in severe combined immunodeficiency disease. Thus, JAK3 has attracted significant attention in recent years as a target for therapeutic intervention in several immune-related diseases. Inhibitors of JAK3 have been developed that might act as either immunosuppressive agents in human organ transplantation or as immunomodulators in autoimmune disorders. We propose that targeting JAK3 offers alternative avenues for the development of new immunomodulatory strategies of therapeutic value. Furthermore, we believe that in addition to the tyrosine kinase domain of JAK3, where inhibitor design efforts are currently focused, non-catalytic regions of JAK3 might represent candidate targets for future drugs.