Mechanism-based inhibitors are relatively chemically inert compounds that become activated when processed by their target enzyme, leading to covalent enzyme inactivation. Fluorine substitution confers a number of properties that are beneficial to the chemistry of such inhibitors and to their potential use as pharmaceuticals, and indeed several fluorinated mechanism-based inhibitors have made it to clinical usage over the past 50 years. Well-known examples are the 5- fluorouracil metabolite, 5-fluoro-2'-deoxyuridine-5'-monophosphate, which is used in the treatment of cancer, and α- difluoromethylornithine for the treatment of African sleeping sickness. As the prevalence of fluorine in medicinal chemistry continues to rise, more and more medically relevant fluorinated mechanism-based inhibitors are being developed with a variety of interesting properties and uses.