Simple SummarySolid cancers are composed of a mixture of various cell types. Tumor cells are among this agglomeration and interact with other components through cell-cell contacts and released factors. Pancreatic cancer is particularly rich in additional cell types which are instructed by neighboring cancer cells to behave in a cancer-promoting manner. One of the abundant cell types in pancreatic cancer are the so called cancer-associated fibroblasts (CAFs). CAFs exist as different subsets with distinct properties which can be tumor growth stimulating or even be tumor restraining. This review describes the various CAF subpopulations, their molecular discrimination, and the resulting functional impact of these cells on pancreatic cancer development and therapy approaches.AbstractPancreatic cancer represents one of the most desmoplastic malignancies and is characterized by an extensive deposition of extracellular matrix. The latter is provided by activated cancer-associated fibroblasts (CAFs), which are abundant cells in the pancreatic tumor microenvironment. Many recent studies have made it clear that CAFs are not a singular cellular entity but represent a multitude of potentially dynamic subgroups that affect tumor biology at several levels. As mentioned before, CAFs significantly contribute to the fibrotic reaction and the biomechanical properties of the tumor, but they can also modulate the local immune environment and the response to targeted, chemo or radiotherapy. As the number of known and emerging CAF subgroups is steadily increasing, it is becoming increasingly difficult to keep up with these developments and to clearly discriminate the cellular subsets identified so far. This review aims to provide a helpful overview that enables readers to quickly familiarize themselves with field of CAF heterogeneity and to grasp the phenotypic, functional and therapeutic distinctions of the various stromal subpopulations.