In the history of drug discovery, the development of covalent inhibitors was for a long time neglected due to safety concerns. This apprehension mostly came from studies revealing that certain compounds, such as bromobenzene or acetaminophen, can form reactive metabolites which covalently bind to liver proteins and cause hepatotoxicity. In spite of these concerns, covalent drugs such as aspirin, beta-lactam antibiotics, or proton-pump inhibitors have proven to be safe and effective. The strength of the covalent interaction between the ligand and the target reduces the off-rate and increases the residence time of the ligand in its target. Therefore, covalent drugs offer certain advantages over classical non-covalent ones. First, the dosage and frequency of treatment can be decreased, potentially reducing side effects. Second, shallow binding pockets, which might not be druggable with noncovalent ligands, can be targeted. As an example, the solvent-exposed K-Ras G12C mutated residue, can be targeted by sotorasib, a reactive Michael acceptor-carrier inhibitor. Third, covalent drugs may be able to bind to protein variants when non-covalent ones fail. For example, irreversible covalent inhibitors of the epidermal growth factor receptor (EGFR) can circumvent acquired resistance to gefitinib. However, they are, of course, very vulnerable to mutation of their covalently-bound amino acid side chain.