The study investigates the role of inflammatory mast cells (MCs) in the angiogenic switch during squamous epithelial carcinogenesis in a mouse model. Expression of HPV16 early region genes in basal keratinocytes of transgenic mice leads to a multistage pathway to squamous carcinoma. The authors found that MC infiltration and activation of matrix metalloproteinase (MMP)-9/gelatinase B coincide with the angiogenic switch in premalignant lesions. MCs are present in hyperplasias, dysplasias, and invasive fronts of carcinomas but not in the core of solid tumors. They release specific serine proteases, MCP-4 (chymase) and MCP-6 (tryptase), which activate progelatinase B and induce angiogenesis. Notably, premalignant angiogenesis is abated in a mast-cell-deficient (KITW/KITW^W^) HPV16 transgenic mouse model. The data suggest that neoplastic progression involves the exploitation of an inflammatory response to tissue abnormality, with MCs playing a key role in activating angiogenesis during the early stages of squamous carcinogenesis.The study investigates the role of inflammatory mast cells (MCs) in the angiogenic switch during squamous epithelial carcinogenesis in a mouse model. Expression of HPV16 early region genes in basal keratinocytes of transgenic mice leads to a multistage pathway to squamous carcinoma. The authors found that MC infiltration and activation of matrix metalloproteinase (MMP)-9/gelatinase B coincide with the angiogenic switch in premalignant lesions. MCs are present in hyperplasias, dysplasias, and invasive fronts of carcinomas but not in the core of solid tumors. They release specific serine proteases, MCP-4 (chymase) and MCP-6 (tryptase), which activate progelatinase B and induce angiogenesis. Notably, premalignant angiogenesis is abated in a mast-cell-deficient (KITW/KITW^W^) HPV16 transgenic mouse model. The data suggest that neoplastic progression involves the exploitation of an inflammatory response to tissue abnormality, with MCs playing a key role in activating angiogenesis during the early stages of squamous carcinogenesis.