The resurgence of covalent drugs is discussed in this review, highlighting their historical success and the need to reassess their potential in drug discovery. Covalent drugs, which form irreversible bonds with their targets, have been successful in treating various conditions but are often overlooked due to safety concerns. The review explores the pharmacological advantages of covalent drugs, such as their ability to achieve high potency and selectivity, and addresses the challenges and risks associated with their use. It introduces the concept of targeted covalent inhibitors (TCIs), which target specific non-catalytic residues on proteins, offering improved selectivity compared to traditional reversible inhibitors. The review also discusses the design and optimization of TCIs, emphasizing the importance of both non-covalent binding affinity and electrophilic reactivity. Finally, it highlights the clinical progress of several covalent drugs, including those in late-stage clinical trials, and emphasizes the potential of TCIs in overcoming drug resistance and improving treatment outcomes.The resurgence of covalent drugs is discussed in this review, highlighting their historical success and the need to reassess their potential in drug discovery. Covalent drugs, which form irreversible bonds with their targets, have been successful in treating various conditions but are often overlooked due to safety concerns. The review explores the pharmacological advantages of covalent drugs, such as their ability to achieve high potency and selectivity, and addresses the challenges and risks associated with their use. It introduces the concept of targeted covalent inhibitors (TCIs), which target specific non-catalytic residues on proteins, offering improved selectivity compared to traditional reversible inhibitors. The review also discusses the design and optimization of TCIs, emphasizing the importance of both non-covalent binding affinity and electrophilic reactivity. Finally, it highlights the clinical progress of several covalent drugs, including those in late-stage clinical trials, and emphasizes the potential of TCIs in overcoming drug resistance and improving treatment outcomes.