Janus kinases (JAKs) phosphorylate cytokine receptors and STAT proteins in the JAK-STAT pathway, which affects cell proliferation, cell death, and immune responses. Dysfunctional JAKs lead to autoimmune diseases such as rheumatoid arthritis. JAK inhibitors have been developed to block abnormal JAK-STAT signaling. New structural data on JAKs allow the design of selective inhibitors that overcome resistance caused by mutations. The review describes the main structural features of JAK with a focus on the active site. It summarizes the JAK inhibitors approved on the market for rheumatoid arthritis and their binding methods. Based on structural analysis, he proposes strategies for new generation JAK inhibitors.