While covalent inhibitors have been used (unintentionally) to inhibit many enzymes, recent covalent inhibitors have primarily targeted kinases. Recent covalent inhibitors have been tried or used as treatments for cancers; some have also been used to treat autoimmune diseases or rheumatoid arthritis. The frequency of cancers, their consequences (severe debilitation and death) and the plethora of cancer types (many of which cannot be addressed by current treatments) provide medical and financial reasons to develop treatments for cancer. If previous treatment modalities have been unsuccessful, then cancers are reasonable indications against which to try novel treatment methods. The severity of many cancers also means that greater side effects may be tolerated in successful cancer drugs than in other drugs that either have less severe symptoms or are chronic and thus require treatment for longer periods of time (although, as noted, covalent drugs may have fewer side effects than the corresponding noncovalent drugs). What developments are important for covalent inhibitors to expand in importance? While covalent inhibitors reacting with residues other than cysteine exist and have been commercialized, few covalent inhibitors are intended to react with lysine, aspartate, glutamate, serine, threonine, and histidine residues. The relative paucity of cysteine residues limits the targets for covalent warheads because cysteines may not be present in a target or may not be effectively positioned to inhibit the protein. Having covalent inhibitors capable of binding to other residues would increase the number of proteins and thus the number of diseases addressable with covalent inhibitors. Vinyl sulfones and vinyl sulfonamides, for example, may be able to react with both cysteine and lysine residues. However, covalent warheads that react with common amino acid side chains may be difficult to incorporate into selective covalent inhibitors; multiple reactive residues may be present in different positions on a protein, requiring other interactions with the target protein to determine selectivity. Data on the reactivity and selectivity will likely be necessary as well. In addition, a broader pool of data on the pharmacokinetics and toxicology of covalent inhibitors would be helpful for both the most common warheads such as acrylamides and aldehydes and newer or less-commonly used warheads. Knowledge of the benefits and liabilities of covalent-binding fragments is necessary to expand the scope of indications beyond cancer, particularly for chronic diseases which require long-term administration of drugs.