Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly lethal disease in humans. Transforming growth factor-β (TGF-β) signaling plays an important role in PDAC progression, as indicated by the fact that Smad4, which encodes a central signal mediator downstream from TGF-β, is deleted or mutated in 55% and the type II TGF-β receptor (Tgfbr2) gene is altered in a smaller subset of human PDAC. Pancreas-specific Tgfbr2 knockout mice have been generated, alone or in the context of active Kras (Kras^G12D) expression, using the Cre-loxP system driven by the endogenous Ptf1a (pancreatic transcription factor-1a) locus. Pancreas-selective Tgfbr2 knockout alone gave no discernable phenotype in 1.5 yr. Pancreas-specific Kras^G12D activation alone essentially generated only intraepithelial neoplasia within 1 yr. In contrast, the Tgfbr2 knockout combined with Kras^G12D expression developed well-differentiated PDAC with 100% penetrance and a median survival of 59 d. Heterozygous deletion of Tgfbr2 with Kras^G12D expression also developed PDAC, which indicated a haploinsufficiency of TGF-β signaling in this genetic context. The clinical and histopathological manifestations of the combined Kras^G12D expression and Tgfbr2 knockout mice recapitulated human PDAC. The data show that blockade of TGF-β signaling and activated Ras signaling cooperate to promote PDAC progression.