Recent evidence has demonstrated that the existence of a cancer stem cell (CSC) subset in a solid tumor is responsible for the progression and relapse of cancer as well as its resistance to current therapies. Over the past decade, CSC research on pancreatic cancer has progressed. A fundamental understanding of pancreatic CSCs may improve therapies and deepen insight into the role of cell-cell interactions within a tumor microenvironment in pancreatic cancer progression. This review focuses on the impact of pancreatic CSCs on the regulatory networks in the tumor microenvironment, and the implications of targeting CSCs to treat pancreatic cancer.