PPIs are involved in diverse biochemical events and perform their functions through the formation of protein-protein complexes or PPI networks. The large and flat interacting surfaces of PPIs make discovery of small-molecule modulators a challenging task. New strategies and more effective chemical technologies are needed to facilitate the development of PPIs small-molecule inhibitors. Covalent modification of a nucleophilic residue located proximally to the immediate vicinity of PPIs can overcome the disadvantages of large interacting surfaces and provides high-affinity inhibitors with increased duration of action and prolonged target modulation. On the other hand, covalent inhibitors that target non-conserved protein residues demonstrate improved selectivity over related protein family members. Herein, we highlight the latest progress of small-molecule covalent PPIs inhibitors and hope to shed light on future PPIs inhibitor design and development. The relevant challenges and opportunities are also discussed.