Click chemistry has emerged as a valuable tool for rapid compound synthesis, presenting notable advantages and convenience in the exploration of potential drug candidates. In particular, in situ click chemistry capitalizes on enzymes as reaction templates, leveraging their favorable conformation to selectively link individual building blocks and generate novel hits. This review comprehensively outlines and introduces the extensive use of click chemistry in compound library construction, and hit and lead discovery, supported by specific research examples. Additionally, it discusses the limitations and precautions associated with the application of click chemistry in drug discovery. Our intention for this review is to contribute to the development of a modular synthetic approach for the rapid identification of drug candidates.