Abstract Improvements in the management of locally advanced or metastatic pancreas cancer have proven to be both difficult and frequently marked by nihilism. Gemcitabine has replaced 5-fluorouracil-based chemotherapy as the standard of care. Gemcitabine first generated improvements in symptom control and survival in advanced disease, spurring further research. Subsequent trials have suggested that combinations of other agents with gemcitabine may extend clinical benefits to larger populations of patients. Newer combined chemoradiotherapy approaches may benefit the small population of patients with resectable disease, as well as the larger number of patients with locally advanced disease. In addition to identifying new cytotoxic agents and biologics, a greater challenge to clinical researchers is the development of innovative tools to diagnose and stage patients with pancreas cancer, and to monitor and assess their response to therapy. This applies not only to individual patients but also to large-scale clinical trials.