Modern drug discovery is contingent on identifying lead compounds and rapidly synthesizing analogues. The use of a common pharmacophore to direct multiple and divergent C-H functionalizations of lead compounds is a particularly attractive approach. Herein, we demonstrate the viability of late-stage diversification through the divergent C-H functionalization of sulfonamides, an important class of pharmacophores found in nearly 200 drugs currently on the market, including the non-steroidal anti-inflammatory blockbuster drug celecoxib. We developed a set of six categorically different sulfonamide C-H functionalization reactions (olefination, arylation, alkylation, halogenation, carboxylation, and carbonylation), each representing a distinct handle for further diversification to reach a large number of analogues. We then performed late-stage, site-selective diversification of a sulfonamide drug candidate containing multiple potentially reactive C-H bonds to synthesize directly novel celecoxib analogues as potential cyclooxygenase-II (COX-2)-specific inhibitors. Together with other recently developed practical directing groups, such as CONHOMe and CONHC(6)F(5), sulfonamide directing groups demonstrate that the auxiliary approach established in asymmetric catalysis can be equally effective in developing broadly useful C-H activation reactions.