The highly regioselective conjugate addition of isoxazol-5-ones to ethenesulfonyl fluoride (ESF) has been developed. In the presence of different bases, N2-alkylated and C4-alkylated isoxazol-5-ones with a sulfonyl fluoride group were obtained separately with good to excellent yields. Further transformations with amines and phenol gave sulfonamides and sulfonates. The intriguing combination of isoxazol-5-ones and the sulfonyl fluoride group produces valuable products for drug discovery.