Pancreatic cancer is the fifth leading cause of adult cancer death in the United States, with 5-year survival rates of only 1% to 4%. Current therapeutic strategies generally result in only a few months of extended life. Recent evidence from several independent laboratories in vitro and in vivo indicate that integrin-mediated cell attachment to the extracellular matrix (ECM), components of which are highly up-regulated in pancreatic cancer, evokes phenotypes and signaling pathways that regulate tumor cell growth and migration. In this review, we will discuss our current understanding of the role of the ECM in directing pancreatic cancer growth, progression, and metastasis. Topics covered include a survey of the existing literature regarding the in vivo and in vitro expression of the ECM and its cell surface receptors, the integrins, in pancreatic cancer; mechanisms involved in the integrin-ECM-mediated malignant phenotype; and future directions for the study of the integrin-ECM axis and its role in pancreatic cancer progression, including potential therapeutic strategies.