Emerging evidence suggests that malignant tumors are composed of a small subset of distinct cancer cells, termed "cancer stem cells" (typically less than 5% of total cancer cells based on cell surface marker expression), which have great proliferative potential, as well as more differentiated cancer cells, which have very limited proliferative potential. Data have been provided to support the existence of cancer stem cells in several different types of cancer, including human blood, brain, prostate, ovarian, melanoma, colon, and breast cancers. We have recently reported the identification of a subpopulation of pancreatic cancer cells that express the cell surface markers CD44+CD24+ESA+ (0.2-0.8% of all human pancreatic cancer cells) that function as pancreatic cancer stem cells. The CD44+CD24+ESA+ pancreatic cancer cells are highly tumorigenic and possess the stem cell-like properties of self-renewal and the ability to produce differentiated progeny. Pancreatic cancer stem cells also demonstrate upregulation of molecules important in developmental signaling pathways, including sonic hedgehog and the polycomb gene family member Bmi-1. Of clinical importance, cancer stem cells in several tumor types have shown resistance to standard therapies and may play a role in treatment failure or disease recurrence. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation.