Since January 2020, Elsevier has established a COVID-19 resource center on Elsevier Connect, providing free information in English and Mandarin about the novel coronavirus. The company has granted permission to make all its COVID-19-related research available in PubMed Central and other public repositories, allowing unrestricted reuse and analysis with acknowledgment of the original source. This permission is valid as long as the resource center remains active. The review focuses on cysteine cathepsins, a family of papain-like cysteine proteases, which play crucial roles in various biological processes. These enzymes are involved in protein turnover, endosomal antigen presentation, and diseases such as cancer and rheumatoid arthritis. They are optimally active in a slightly acidic environment and exhibit broad specificity, cleaving substrates after basic or hydrophobic residues. The review covers the structure and specificity of cysteine cathepsins, including their substrate binding sites and the development of small-molecule inhibitors. Recent advances in understanding substrate specificity and the use of activity-based probes for monitoring enzyme activity in biological systems are also discussed.Since January 2020, Elsevier has established a COVID-19 resource center on Elsevier Connect, providing free information in English and Mandarin about the novel coronavirus. The company has granted permission to make all its COVID-19-related research available in PubMed Central and other public repositories, allowing unrestricted reuse and analysis with acknowledgment of the original source. This permission is valid as long as the resource center remains active. The review focuses on cysteine cathepsins, a family of papain-like cysteine proteases, which play crucial roles in various biological processes. These enzymes are involved in protein turnover, endosomal antigen presentation, and diseases such as cancer and rheumatoid arthritis. They are optimally active in a slightly acidic environment and exhibit broad specificity, cleaving substrates after basic or hydrophobic residues. The review covers the structure and specificity of cysteine cathepsins, including their substrate binding sites and the development of small-molecule inhibitors. Recent advances in understanding substrate specificity and the use of activity-based probes for monitoring enzyme activity in biological systems are also discussed.