Several small-molecule inhibitors of the SARS-CoV-2 M pro have been discovered, with a few progressing into early phase human clinical trials. The fundamental aim of these inhibitors is to disrupt the viral life cycle. One therapeutic strategy is to design inhibitors with electrophilic functional groups (a.k.a., "warhead") that bind to the nucleophilic active site cysteine (Cys145) of the M pro target. Cys145 of the M pro is essential for catalytic activity, so blockage or modification of this residue is detrimental to the virus. This strategy of targeted covalent modification of druggable sites in disease targets is gaining traction in drug discovery, as evidenced by the successful number of approved drugs employing this approach (e.g., ibrutinib). Importantly, covalent inhibitors offer superior potencies, prolonged duration of therapeutic action, and high target selectivity than their non-covalent drug binding counterparts. Also, since such covalent binding events can be chemically tuned to be reversible, concerns regarding the risk of potential off-target reactivity and toxicity can be mitigated while maintaining potency and efficacy.