Proteases can regulate many aspects of tumor development as their actions, which include degradation of the extracellular matrix, proteolytic processing of chemokines and activation of other enzymes, influence several key tumorigenic processes. Members of one protease class, the cysteine cathepsins, have received increasing recognition for their involvement in cancer development, and numerous clinical studies have reported correlations between elevated cathepsin levels and malignant progression. This is also the case for cathepsin H, a member of the cysteine cathepsin family, and its utility as a prognostic marker has been analyzed extensively. However, there is limited information available on its specific functions in tumor development and progression. To gain further insight into the role of this protease in cancer, we crossed cathepsin H-deficient mice with the RIP1-Tag2 model of pancreatic islet carcinogenesis. Deletion of cathepsin H significantly impaired angiogenic switching of the pre-malignant hyperplastic islets and resulted in a reduction in the subsequent number of tumors that formed. Moreover, the tumor burden in cathepsin H null RT2 mice was significantly reduced, in association with defects in the blood vasculature and increased apoptosis. Thus, we demonstrate here for the first time important tumor-promoting roles for cathepsin H in vivo using a mouse model of human cancer.