Pharmaceutical research for drug discovery has recently begun to investigate the potential of covalent inhibitors after years of mostly focusing on non-covalent reversible inhibitors. The initial reluctance to develop covalent inhibitors as drugs was due to fear of irreversible damage as well as toxicity arising from off target effects In fact, most covalent drugs have resulted from serendipitous discovery rather than by deliberate design. Conventional non-covalent drugs interact reversibly with targets via interactions that are weak and transient (van der Waals interactions and hydrogen bonds). On the other hand, covalent inhibitors form strong covalent bonds to target proteins (Figure ). Broadly speaking, a covalent inhibitor can be divided into two distinct parts: the "warhead" or "reactive group" which form the covalent bond to their targets and the "guidance system" which determines the selectivity of the inhibitor for its target (Figure ). Reactive groups are most commonly electrophilic because most of the potential reactive sites on a target protein (either the N-terminal amino groups or amino acid side chains) are nucleophilic in nature. Reactive groups must follow the Goldilocks principlethey must be reactive enough to form a bond to a target upon complex formation but not reactive enough to form bonds to other protein targets or functional groups when unbound.