Pancreatic cancer remains one of the most difficult malignancies to treat. Significant developments in our understanding of pancreatic cancer biology have occurred over the past decade. One of the key advances has been the formulation of the cancer stem cell model of tumor growth and subsequent experimental proof of pancreatic cancer stem cell existence. Cancer stem cells contribute to pancreatic tumor growth and progression and are at least partially responsible for the relative resistance of the tumor to systemic chemotherapy and radiation. Significant questions remain about how the mutational profile of the tumor, the tumor microenvironment, and normal pancreatic developmental pathways contribute to pancreatic cancer stem cell biology. Answers to these questions will likely yield new therapeutic approaches for this deadly disease.