Context.—Metastatic disease is the most critical determinant of resectability of pancreatic cancer and accounts for the poor outcome of patients with this disease. Thus, a better understanding of metastatic pancreatic cancer will afford new opportunities for therapeutic intervention.

Objective.—To summarize and discuss the current understanding of the clinical and molecular features of metastatic pancreatic cancer.

Data Sources.—Published literature on advanced stage pancreatic cancer, pancreatic cancer metastasis, and autopsy findings in patients with pancreatic cancer.

Conclusions.—In the clinical setting, it can be difficult to distinguish a metastatic pancreatic carcinoma from primary neoplasms in the liver, lung, or ovary. However, immunolabeling for DPC4 protein as part of a diagnostic panel is useful for making this distinction. Emerging data from a variety of investigators now indicate that overexpression of EphA2, loss of DPC4 and MKK4, and aberrant activation of the Hedgehog signaling pathway are associated with metastatic propensity of pancreatic cancers, providing novel therapeutic targets for the most lethal stage of this disease.