Despite considerable progress, PDA carries a dismal prognosis. Recent advances in clinical and basic science have revealed new insights into pancreatic carcinogenesis. Compelling histopathological and molecular evidence support the evolution of PDA through a series of noninvasive duct lesions named PanINs. Progression of PanIN lesions is associated with genetic and biochemical aberrations correlating with advancing cellular atypia from early stages to invasive cancer. Several studies with pancreatic resection specimens revealed a sequence of genetic changes including activating K-ras mutations, overexpression of the growth factor receptor HER-2/neu, and the inactivation of the tumor suppressor genes INK4A/ARF, TP53, Smad4/DPC4, and BRCA2. The availability of mouse models mimicking human pancreatic cancer allows functional studies which will evaluate relevance for the human disease. Moreover, the precise knowledge of critical events in pancreatic carcinogenesis opens new horizons in designing new diagnostic and therapeutic strategies against this fatal disease.