The contribution of extracellular proteolysis to processes of tumor invasion and metastasis has been recognized for more than 20 years. However, after millions of dollars and untold hours of investment in preclinical research and the development of broad range inhibitors of MMPs, clinical trials of late-stage tumor patients show no indication that this approach will be successful. In the basic science arena, there have been stunning advancements that illustrate novel biological activities for proteases and that suggest they are key regulators of many physiological and pathological processes. The Proteases and Cancer: Biology and Therapeutics Workshop (held in Bethesda, MD, November 20–22, 2002) was organized by the Division of Cancer Biology, National Cancer Institute (NCI) to identify research areas and directions that will accelerate understanding protease biology and enhance clinical translation. The overall consensus was that protease biology represents fertile ground for advances that will be clinically useful but perhaps not for the reasons or purpose originally thought. Protease-related technologies show particular promise for the detection, prognosis, and prevention of cancer, and for therapeutic purposes in defined situations. Promising areas for further research are identified, and specific recommendations for the development of a consortium to coordinate the efforts of the protease community are made.