Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest epithelial malignancies. Improvements in our understanding of PDAC carcinogenesis will hopefully improve its detection, management, and outcomes, as has been achieved with other malignancies. Here we review the literature on the natural history of PDAC, including its cell of origin, the initiating somatic mutational events, pathways deranged in the mature tumor, its biological heterogeneity, and the relationship of the primary tumor with metastases. We also suggest areas for further research and highlight translatable findings that are beginning to make clinical inroads.