The extraordinary advances in the basic science of immunology have provided therapeutic approaches that have revolutionized outcomes in patients with inflammatory and immune-mediated diseases. These include numerous successful therapeutic monoclonal antibodies and engineered recombinant cytokine receptors. Advances in deciphering the biochemical pathways of immune cell signaling similarly led to the generation of small molecule therapies that complement biologics. In this Review, we focus on protein kinase inhibitors and their use in immune-mediated and inflammatory disorders. Although this field has been reviewed numerous times, it moves extraordinarily quickly, with over 60 small molecule protein kinase inhibitors now approved and hundreds more in development6. We provide a brief history of targeted kinase inhibitors, which first emerged for the treatment of cancer. We then discuss how purposefully targeting signal transduction pathways used by major classes of immunoreceptors has led to the effective treatment of numerous immune-mediated disorders. We focus on Janus kinase (JAK) inhibitors as they comprise one of the most active and successful areas, but we also review the successful targeting of TEC family kinases and other emerging protein kinase drug targets. We compare the ways in which kinase inhibitors may be similar yet distinct from biologics targeting cells and cytokines, and we consider future approaches and opportunities in this field.