<p>Diversity oriented clicking (DOC) is an organic chemistry strategy designed to create structurally and functionally diverse small molecules to explore chemical space and discover novel bioactive compounds. The approach combines classical click reactions and fluoride exchange chemistry, in which fluorine atoms bound to sulfur or phosphorus serve as highly selective reaction handles. This combination enables the formation of covalent bonds rapidly and under mild, biocompatible conditions, broadening the synthetic toolkit for building molecular complexity. Compound libraries generated through DOC hold particular promise in drug discovery, where they accelerate the profiling of protein function in disease contexts and streamline the design, synthesis and high-throughput screening of novel therapeutic candidates. In this Primer, we outline the principles behind this synthesis strategy, describe key DOC-compatible functional groups, and highlight examples where DOC and fluoride exchange have been instrumental in probing human disease.</p>