Abstract: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer mortality in the United States and has an average survival of only 6 months. PDAC is characterized by progression through defined histologic precursor lesions and a spectrum of recurrent genetic mutations, including early and universal oncogenic mutations in KRAS as well as frequent inactivation of the p16INK4A, p14 ARF, p53 and SMAD4 tumor suppressor genes. Additionally the pancreatic cancer genome is highly aneuploid and characterized by non-reciprocal translocations and recurrent amplifications and deletions. The work described in this dissertation aims to elucidate the genetic determinants of PDAC. First, we have developed mouse models of PDAC that recapitulate hallmark genetic and pathologic features of the human disease. We show that oncogenic KrasG12D initiates preinvasive pancreatic intraepithelial neoplasms (PanIN) and that progression of these PanIN lesions to invasive and metastatic adenocarcinoma is restrained by the p16Ink4a-Rb and p19Arf-p53 tumor suppressor pathways. We further demonstrate that the tumor suppressor genotype in these mouse models of PDAC determines the clinical, pathologic and genomic features of the resultant tumors. Second, we present a high-resolution characterization of the human pancreatic adenocarcinoma genome using an integrated approach of array-comparative genomic hybridization (ACGH) combined with expression profiling. We have identified numerous chromosomal copy number alterations (CNAs) in the form of recurrent amplifications and deletions in both primary tumors and cell lines. Additionally, we demonstrate that CNAs have a powerful effect on global gene expression patterns, with amplification driving overexpression and deletion resulting in loss of expression of many affected genes. Lastly, we show that the integrated application of ACGH and expression profiling of amplified and deleted genes provides a productive entry point for discovery of novel cancer-relevant genes that may give rise to important diagnostic and therapeutic opportunities for improved clinical management of this disease.