Since January 2020, Elsevier has created a free COVID-19 resource center with English and Mandarin information on the novel coronavirus. The center is hosted on Elsevier Connect, the company's public news and information website. Elsevier grants permission to make all its COVID-19-related research immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database, for unrestricted research reuse and analysis. These permissions are granted free of charge as long as the center remains active. The article reviews cysteine cathepsins, a family of papain-like cysteine proteases. These enzymes have unique reactive-site properties and uneven tissue-specific expression. Their activity is a balance of expression, targeting, zymogen activation, inhibition by protein inhibitors, and degradation. Their substrate-binding site specificity, small-molecule inhibitor repertoire, and crystal structures provide new research tools. Cysteine cathepsins are important regulators and signaling molecules in numerous biological processes. The current challenge is to identify their endogenous substrates to understand substrate degradation and processing mechanisms. Cysteine cathepsins are optimally active in slightly acidic pH and are mostly unstable at neutral pH. When outside lysosomes or extracellularly, they can be rapidly inactivated at neutral pH. Cathepsin S is stable at neutral or slightly alkaline pH. The inactivation of cathepsin L, the most unstable at neutral pH, is a first-order process. Cysteine cathepsins are found in various cellular compartments, including the nucleus, cytoplasm, and plasma membrane. They play roles in cell-cycle regulation and proteolytic processing of histone H3 tails. Cysteine cathepsins are involved in protein turnover, endosomal antigen presentation, and diseases like cancer and rheumatoid arthritis. They are also involved in collagen remodeling and bone resorption. Their specific physiological functions may be at least partially attributed to their differences in localization inside and outside cells. Cysteine cathepsins are important in various biological processes, including intracellular protein degradation, antigen processing, and immune responses. The review highlights recent advances in understanding their structure, specificity, and interactions with substrates. It also discusses the development of small-molecule inhibitors and activity-based probes for studying their functions.Since January 2020, Elsevier has created a free COVID-19 resource center with English and Mandarin information on the novel coronavirus. The center is hosted on Elsevier Connect, the company's public news and information website. Elsevier grants permission to make all its COVID-19-related research immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database, for unrestricted research reuse and analysis. These permissions are granted free of charge as long as the center remains active. The article reviews cysteine cathepsins, a family of papain-like cysteine proteases. These enzymes have unique reactive-site properties and uneven tissue-specific expression. Their activity is a balance of expression, targeting, zymogen activation, inhibition by protein inhibitors, and degradation. Their substrate-binding site specificity, small-molecule inhibitor repertoire, and crystal structures provide new research tools. Cysteine cathepsins are important regulators and signaling molecules in numerous biological processes. The current challenge is to identify their endogenous substrates to understand substrate degradation and processing mechanisms. Cysteine cathepsins are optimally active in slightly acidic pH and are mostly unstable at neutral pH. When outside lysosomes or extracellularly, they can be rapidly inactivated at neutral pH. Cathepsin S is stable at neutral or slightly alkaline pH. The inactivation of cathepsin L, the most unstable at neutral pH, is a first-order process. Cysteine cathepsins are found in various cellular compartments, including the nucleus, cytoplasm, and plasma membrane. They play roles in cell-cycle regulation and proteolytic processing of histone H3 tails. Cysteine cathepsins are involved in protein turnover, endosomal antigen presentation, and diseases like cancer and rheumatoid arthritis. They are also involved in collagen remodeling and bone resorption. Their specific physiological functions may be at least partially attributed to their differences in localization inside and outside cells. Cysteine cathepsins are important in various biological processes, including intracellular protein degradation, antigen processing, and immune responses. The review highlights recent advances in understanding their structure, specificity, and interactions with substrates. It also discusses the development of small-molecule inhibitors and activity-based probes for studying their functions.