This study investigates the cooperative interactions between two signature mutations in pancreatic ductal adenocarcinoma: activated Kras and Ink4a/Arf deficiency. In mice engineered to express a mutant Kras allele (KrasG12D) specifically in the pancreas and to delete the Ink4a/Arf tumor suppressor allele, KrasG12D expression alone led to the development of focal premalignant ductal lesions (PanINs), while Ink4a/Arf deficiency alone did not produce any neoplastic lesions. However, when both mutations were combined, they resulted in an earlier appearance of PanIN lesions that rapidly progressed to highly invasive and metastatic cancers, leading to death in all cases by 11 weeks. The tumors exhibited features similar to human pancreatic ductal adenocarcinoma, including a proliferative stromal component and ductal lesions prone to advance to a poorly differentiated state. This mouse model provides experimental support for the widely accepted model of human pancreatic adenocarcinoma, where activated KRAS initiates PanIN lesions and INK4A/ARF tumor suppressors constrain the malignant conversion of these lesions into lethal ductal adenocarcinoma. The model may also facilitate the systematic analysis of genetic lesions implicated in human disease and the identification of early disease markers and novel therapies.This study investigates the cooperative interactions between two signature mutations in pancreatic ductal adenocarcinoma: activated Kras and Ink4a/Arf deficiency. In mice engineered to express a mutant Kras allele (KrasG12D) specifically in the pancreas and to delete the Ink4a/Arf tumor suppressor allele, KrasG12D expression alone led to the development of focal premalignant ductal lesions (PanINs), while Ink4a/Arf deficiency alone did not produce any neoplastic lesions. However, when both mutations were combined, they resulted in an earlier appearance of PanIN lesions that rapidly progressed to highly invasive and metastatic cancers, leading to death in all cases by 11 weeks. The tumors exhibited features similar to human pancreatic ductal adenocarcinoma, including a proliferative stromal component and ductal lesions prone to advance to a poorly differentiated state. This mouse model provides experimental support for the widely accepted model of human pancreatic adenocarcinoma, where activated KRAS initiates PanIN lesions and INK4A/ARF tumor suppressors constrain the malignant conversion of these lesions into lethal ductal adenocarcinoma. The model may also facilitate the systematic analysis of genetic lesions implicated in human disease and the identification of early disease markers and novel therapies.