In theory, any enzyme or protein can be inhibited using a covalent inhibitor; nearly all proteins possess an N-terminus and amino acid side chains amenable to reaction with electrophiles. However, previous concerns about off-target toxicity and immune sensitization by covalent drugs mean that they are not used when a noncovalent drug is effective. Many of the enzymes that are important drug development targets are not readily inhibited by noncovalent drugs, making other design strategies necessary. Kinases, for example, have ATP binding sites for which enzyme selectivity is difficult to obtain, and have protein-protein interaction sites with large surface areas and limited interaction densities that make small molecule inhibitor design difficult. Covalent inhibitors have thus been developed for a variety of kinases, including KRAS, Bruton's tyrosine kinase (BTK), epidermal growth factor receptor (EGFR), Janus kinase 3 (JAK3), c-Jun N-terminal kinases (JNK1-3), phosphoinositide 3-kinases (PI3Kα), vascular endothelial growth factor receptor 2 (VEGFR2), SRC proto-oncogene tyrosine-protein kinase (SRC), never in mitosis, gene A (NIMA) related kinase 2 (NEK2), extracellular signal-regulated kinase (ERK1-2), FMS-like tyrosine kinase 3 (FLT3), AKT (or protein kinase B; PKB), and transforming growth factor-β (TGFβ)-activated kinase (TAK). Targets previously considered undruggable such as KRAS (G12C), Myc and STAT5 (can now be successfully targeted using covalent inhibitors. Nirmatrelvir is a covalent inhibitor of the main SARS-CoV-2 protease 3CL PRO , while telaprevir, boceprevir, and narlaprevir are covalent inhibitors of the hepatitis C viral protease NS3/4a. Voxelotor alters sickle-cell hemoglobin through reaction with the N-terminus of the hemoglobin α-chain. The apoptosis regulator protein MCL1 30 , the tyrosine kinases ErbB2 (HER2) and ErbB4 1 , and carboxylesterases have all been targets of covalent inhibitors.