Click chemistry is an immensely powerful technique for the synthesis of reliable and efficient covalent linkages. When undertaken in living cells, the concept is thereby coined bioorthogonal chemistry. Used in conjunction with the photo-cross-linking methodology, it serves as a sound strategy in the exploration of biological processes and beyond. Its broad scope has led to widespread use in many disciplines; however, this Review focuses on the use of click and bioorthogonal chemistry within medicinal chemistry, specifically with regards to drug development applications, namely, the use of DNA-encoded libraries as a novel technique for lead compound discovery, as well as the synthesis of antisense oligonucleotides and protein-drug conjugates. This Review aims to provide a critical perspective and a future outlook of this methodology, such as potential widespread use in cancer therapy and personalized medicine.