Activating KRAS mutations and p16^Ink4a inactivation are near universal events in human pancreatic ductal adenocarcinoma (PDAC). In mouse models, Kras^G12D initiates formation of premalignant pancreatic ductal lesions, and loss of either Ink4a/Arf (p16^Ink4a/p19^Arf) or p53 enables their malignant progression. As recent mouse modeling studies have suggested a less prominent role for p16^Ink4a in constraining malignant progression, we sought to assess the pathological and genomic impact of inactivation of p16^Ink4a, p19^Arf, and/or p53 in the Kras^G12D model. Rapidly progressive PDAC was observed in the setting of homozygous deletion of either p53 or p16^Ink4a, the latter with intact germ-line p53 and p19^Arf sequences. Additionally, Kras^G12D in the context of heterozygosity either for p53 plus p16^Ink4a or for p16^Ink4a/p19^Arf produced PDAC with longer latency and greater propensity for distant metastases relative to mice with homozygous deletion of p53 or p16^Ink4a/p19^Arf. Tumors from the double-heterozygous cohorts showed frequent p16^Ink4a inactivation and loss of either p53 or p19^Arf. Different genotypes were associated with specific histopathologic characteristics, most notably a trend toward less differentiated features in the homozygous p16^Ink4a/p19^Arf mutant model. High-resolution genomic analysis revealed that the tumor suppressor genotype influenced the specific genomic patterns of these tumors and showed overlap in regional chromosomal alterations between murine and human PDAC. Collectively, our results establish that disruptions of p16^Ink4a and the p19^ARF-p53 circuit play critical and cooperative roles in PDAC progression, with specific tumor suppressor genotypes provocatively influencing the tumor biological phenotypes and genomic profiles of the resultant tumors.