Over the past decade, sulfonyl fluoride exchange (SuFEx) chemistry has seen an increase in popularity owing to its use as a biocompatible "click" reaction. First introduced in 2014, SuFEx chemistry relies upon the exchange of an incoming nucleophile with fluoride on a hexavalent sulfur forming an irreversible, covalent bond. This exchange, however, must occur under catalytic conditions whereby both the sulfonyl group and departing fluoride group are stabilized by hydrogen bonding. This imparts a degree of stability and selectivity on sulfonyl fluorides (SFs) not seen with other electrophilic groups such as sulfonyl chlorides, epoxides, and acrylamides. When placed in the context of an enzyme active site, this catalytic condition is the hydrogen bonding associated with donor residues surrounding the nucleophilic residue of interest. This quiescent affinity model requires that the sulfonyl fluoride first establishes noncovalent interactions before undergoing nucleophilic attack. This selectivity and click-like reactivity of SFs has led to their incorporation into pharmaceutically active drug molecules and biochemical probes. Although SFs contain enhanced stability under physiological conditions, their use is often complicated by their incompatibility to various common synthetic conditions such as nucleophiles, base, and high temperature. This results in SFs being incorporated onto a core scaffold late in the synthetic route. There are two main approaches for introducing sulfonyl fluorides in a synthetic route: first, a premade aryl SF is often coupled to a pendant group (such as an amine) through amide bond formation or amine alkylation (Figure ). Examples of this approach is evident in the synthesis of inhibitors for xIAP, MCL-1, BCL-1, and HSP27. Although this approach offers high yields, it relies on the commercial availability of the aryl sulfonyl fluoride, thus restricting the functional diversity possible. Furthermore, this Copper coupling for SPG synthesis c. Dual photocatalysis coupling 1 2 3 d. Thioether oxidation route e. Alkyl sulfonylation 1 2 3 4 5 6 1a 2a 3a 4a 5a 6a