Commonly used immunosuppressants possess several significant dose-limiting toxicities, prompting the search for agents whose mechanisms of action are limited to immune cells. Inhibition of Janus Kinase 3 (JAK3), a hematopoetic cell-restricted tyrosine kinase, represents an attractive target for immunosuppression owing to its limited distribution in tissue and specific role in lymphoid homeostasis. CP-690,550, a JAK3 inhibitor undergoing clinical trials for the treatment of transplant rejection and autoimmune disorders, has shown efficacy similar to comparator immunosuppressants. However, its inhibition of the more ubiquitous JAK family members, JAK1 and JAK2, is a probable cause of drug-related adverse events (e.g. overt immunosuppression, anemia). Here, we argue that CP-690,550 represents only a starting point in the search for a safer small molecule immunosuppressant, and that an isozyme-selective JAK3 inhibitor identified by rational drug design might be substantially safer.