Here we discuss the therapeutic potential of Janus kinase 3 (JAK3) inhibitors as a new class of immunomodulatory agents with immunosuppressive, anti-inflammatory, anti-allergic, anti-thrombotic and anti-leukemic properties. JAKs are abundantly expressed in primary leukemic cells from children with ALL (acute lymphoblastic leukemia) and are crucial for signals regulating apoptosis. Additional roles for JAK3 in mast cell-mediated immediate hypersensitivity reactions, autoimmune disorders and platelet function have recently been described. The preclinical studies on JAK3 inhibitors revealed their clinical potential as anti-leukemic agents with anti-thrombotic, anti-allergic and immunosuppressive properties. Results from multiple preclinical experimental model systems of autoimmune diabetes, pancreatic islet transplantation, solid organ transplantation, allergy, thrombosis and bone marrow transplantation are discussed in the context of the clinical need for new immunomodulatory agents with such properties.