Mutations in KRAS-one of the ras family of oncogenes, encoding a GTPase critical to intracellular signal transduction--are more prevalent (80%-95%) in pancreatic cancer than in any other malignancy. There is increasing evidence that stromal cells--including pancreatic stellate cells--play a vital role in development and progression of pancreatic carcinomas. Advances in understanding the underlying biology of tumor-stroma interactions and tumor heterogeneity are critical to guiding rational approaches to designing treatments tailored to targeting KRAS in the stroma-rich microenvironment. Areas of interest in creating novel approaches to therapy include elucidating interactions of KRAS with microRNAs, the role of intratumoral hypoxia, and exploration of diverse modes of intercellular propagation of signals that stimulate malignant invasion and metastasis. This article provides an overview and state-of-the-art update of knowledge regarding pancreatic tumor biology, with a special focus on pancreatic tumor heterogeneity, the role of microRNA-mediated and hypoxic alterations in gene expression and interactions with KRAS, intercellular communication and trafficking, and progress in understanding KRAS as a potential target for pancreatic cancer therapy.