Recent work has been devoted to reduce the safety liabilities of covalent drugs resulting from off-target binding by tuning ligands to specific binding sites. This can be achieved through developing targeted covalent inhibitors (TCIs) with high selectivity. The binding of a covalent drug usually consists in the reaction of an electrophilic warhead of the ligand with a nucleophilic sidechain in the protein, such as acrylamides reacting with cysteines. By choosing specific chemical functions (warheads) and optimizing the combination of re-activity with target complementarity, it has become possible to tailor covalent drugs for specific targets, reducing safety concerns. For instance, this can be achieved through fragment-based drug discovery methods applied to covalent compounds. Innovative chemical biology tools for validating the activity, selectivity, and toxicity of covalent ligands have been developed over the last decade and provide a toolbox for charting new territories in drug design. Due to their advantages, a renaissance in the development of covalent drugs occurred in recent years (Figure ). Recent Food and Drug Administration (FDA) approvals include a range of rationally designed covalent inhibitors in different indications such as cancer, viral diseases, and sickel-cell anaemia. For example, in 2021 and 2022, the FDA approved the first two anti-cancer therapeutics targeting G12C-mutated K-Ras, sotorasib and adagrasib.