Great inroads have been made in defining the oncogenic pathways intrinsic to neoplastic cells and the mechanisms by which they are activated in tumors. Knowledge of these pathways provides numerous opportunities that are actively being pursued to develop targeted therapies for cancer. Complementary studies, focused on the non-transformed components of the tumor microenvironment (TME), have revealed that the extrinsic cues provided by the TME are also essential for tumor cells to manifest a fully transformed phenotype, angiogenesis and metastasis. Delineation of these cues and their underlying cellular and molecular pathways will thus lead to a new era of integrative cancer therapy based on combinatorial drug regimens that act synergistically to destroy the neoplastic cells by targeting both the intrinsic and extrinsic pro-oncogenic pathways. Tumor-associated fibroblasts (TAFs) and proteases are two of the key regulators of epithelial-derived tumors that represent potential targets of such integrative therapies. Herein, we consider the potential therapeutic benefit of inhibiting the function of fibroblast activation protein (FAP), a cell surface serine protease with dipeptidyl peptidase and endopeptidase activity that is expressed on TAFs and pericytes, in an integrative approach to treating cancer.