Pancreatic ductal adenocarcinoma remains an extremely aggressive malignancy that is virtually therapy-resistant and has therefore one of the worst prognoses of all human cancers. The focus of research, which had been placed mostly on genetic and epigenetic alterations of the cancer cells themselves, has shifted gradually towards the microenvironment. The cancer microenvironment consists of various components, including fibroblasts, endothelial cells, immune cells, and endocrine cells, that interact with each other and the cancer cells in a complex fashion. This interplay has implications for pancreatic cancer cell growth, migration and invasion, angiogenesis, and immunological recognition of cancer cells. Evidence is accumulating that the cancer microenvironment plays an active role in disease progression, and efforts are being made to target this interplay between cancer cells and host cells to improve the outcome of this deadly disease.