Pfizer’s ritlecitinib, a first-in-class, selective, oral covalent inhibitor of JAK3 and the TEC family of kinases, was FDA-approved in June 2023 for the treatment of severe alopecia areata. Ritlecitinib, previously highlighted as a May 2023 Molecule of the Month, derives its JAK-family kinase selectivity from the covalent modification of a unique cysteine on JAK3 and is strongly active despite weak, micromolar binding affinity due to a relatively high kinetic rate of inactivation. This annotation reviews the discovery of ritlecitinib, highlighting the interpretation of selectivity assays, the PK optimization required due to the short resynthesis rate of JAK3, the evolution of the JAK3 therapeutic hypothesis, and how this 2023 Molecule of the Year nominee has become a classic case study for covalent drug discovery.