Cysteine cathepsins are a family of proteases that are frequently upregulated in various human cancers, including breast, prostate, lung, and brain. Indeed, elevated expression and/or activity of certain cysteine cathepsins correlates with increased malignancy and poor patient prognosis. In normal cells, cysteine cathepsins are typically localized in lysosomes and other intracellular compartments, and are involved in protein degradation and processing. However, in certain diseases such as cancer, cysteine cathepsins are translocated from their intracellular compartments to the cell surface and can be secreted into the extracellular milieu. Pharmacological studies and in vitro experiments have suggested general roles for the cysteine cathepsin family in distinct tumorigenic processes such as angiogenesis, proliferation, apoptosis, and invasion. Understanding which individual cathepsins are the key mediators, what their substrates are, and how they may be promoting these complex roles in cancer are important questions to address. Here, we discuss recent results that begin to answer some of these questions, illustrating in particular the lessons learned from studying several mouse models of multistage carcinogenesis, which have identified distinct, tissue-specific roles for individual cysteine cathepsins in tumor progression.