During the past decade, covalent targeting has experienced a revival, especially in the kinase field. Addressing non-conserved cysteine residues by targeted covalent inhibitors has enabled the design of ligands with high selectivity in the kinome and has led to five currently approved drugs (1–5; early September 2018). Covalent inhibition was also the prime strategy for the selective targeting of JAK3, a member of the Janus kinase (JAK) family of non-receptor tyrosine kinases. JAKs are key regulators of the immune system. However, while the function of JAK3 is mainly limited to immune signaling, the remaining three JAK family members also fulfill other essential functions outside the immune system. Therefore, JAK3 has long been discussed as a promising target for the treatment of inflammatory and autoimmune disorders with limited side effects. Until recently, however, the development of sufficiently JAK3-selective small molecules was impeded by the high similarity of the JAKs’ ATP binding pockets. Addressing Cys909, which is a serine in the other JAK family members, with electrophilic warheads, has recently enabled the generation of JAK3 inhibitors with unprecedented selectivity in the JAK family and the kinome. These compounds have now paved the way for the in-depth examination of JAK3-dependent signaling in cells and in vivo. Current research efforts culminated in the development of PF-06651600, a phase II clinical candidate from Pfizer under investigation for the treatment of rheumatoid arthritis, inflammatory bowel disease, and alopecia areata.