Here, we demonstrate the potent capabilities of oxetane sulfonyl fluorides (OSF) and azetidine sulfonyl fluorides (ASF) as versatile, customizable reagents for the generation of a diverse array of novel pharmacophore motifs (Figure ). The facile generation of carbocations from OSF reagents is exploited to synthesize several novel oxetane analogues of biologically active molecules and marketed drugs. We present the inaugural synthesis of ASFs and demonstrate their compatibility with the deFS coupling chemistry, offering an attractive alternative to azabicyclo[1.1.0]butane (ABB) reagents and their derivatives. Control of solvent and nucleophile strength unlocks the previously challenging SuFEx reaction pathway for these reagents, resulting in novel strained ring S(VI) motifs. Finally, we demonstrate the potential applications in forming new degrader motifs or PROTAC linker units through coupling with E3 ligase ligands. With a repertoire exceeding 100 novel oxetane and azetidine fragments, our study underlines the synthetic versatility of oxetane and azetidine sulfonyl fluorides as a flexible platform to facilitate access to innovative chemical space in drug discovery.