The protease cathepsin B (CTSB) has previously been shown to be crucial for mammary tumorigenesis in the mouse mammary tumour virus–polyoma middle T antigen (MMTV–PyMT) mouse model. Ruffell et al. now report that CTSB loss does not affect development of squamous cell carcinomas (SCCs) in mice that express human papillomavirus type 16 (HPV-16) oncoproteins in squamous epithelial cells (K14-HPV-16 mice). Conversely, cathepsin C (CTSC) loss slowed the growth of SCCs in K14-HPV-16 mice, and CTSC loss had no effect on MMTV–PyMT mediated tumorigenesis. Therefore, tissue context is important in defining the functional roles of these enzymes.