The data presented here identify palladin as the mutated gene in the pancreatic cancer susceptibility locus at 4q32–34, validate abnormal expression of the gene in a familial pancreatic cancer kindred, demonstrate RNA overexpression of this gene in sporadic pancreatic cancers and precancerous pancreatic tissues, characterize the functional changes induced by the mutant protein, and suggest that cytoskeletal abnormalities may be a driving force in pancreatic oncogenesis. The gene discussed is PALLD; the disease is familial pancreatic carcinoma.