Genetically engineered mouse (GEM) models of cancer have progressively improved in technical sophistication and accurately recapitulating the cognate human condition and have had a measurable impact upon our knowledge of tumorigenesis. However, the application of such models toward the development of innovative therapeutic and diagnostic approaches has lagged behind. Our laboratory has established accurate mouse models of early and advanced ductal pancreatic cancer by conditionally expressing mutant K-ras and Trp53 alleles from their endogenous promoters in pancreatic progenitor cells. These K-Ras-dependent preclinical models provide valuable information on the cell types and pathways involved in the development of pancreatic cancer. Furthermore, they can be used to investigate the molecular, cellular, pharmacokinetic, and radiological characteristics of drug response to classical chemotherapeutics and to targeted agents. This chapter reviews the methods used to explore issues of drug delivery, imaging, and preclinical trial design in our GEM models for pancreatic cancer. We hypothesize that results of our preclinical studies will inform the design of clinical trials for pancreatic cancer patients.