The histopathologic distinction of ductal adenocarcinoma (DA) of the pancreas from chronic pancreatitis (CP) is a well-known challenge. Several parameters have been determined by the authors and other investigators to be useful in this distinction. The findings that are entirely diagnostic for DA are perineural and vascular invasion; however, they are rarely detectable in biopsy specimens. The most common findings that are highly suggestive of DC and can also be expected in biopsy specimens include random distribution of ductal structures, irregular ductal contours, nuclear enlargement (>3 times the size of a lymphocyte), and pleomorphism, distinct nucleoli, and mitosis. Other, somewhat rarer findings are uninterrupted proliferation of numerous (>50) ducts, intraluminal necrotic cellular debris, hyperchromatic raisinoid nucleoli, the presence of naked ducts in fat without surrounding pancreatic elements or fibrous tissue, and ducts lying adjacent to arterioles. Findings that favor a benign process over an invasive carcinoma are: lobular architecture with clusters of evenly spaced ductal units, uniformly sized ductal elements, smooth ductal contours, ducts surrounded by acini or islets, and intraluminal mucoprotein plugs. Combinations of these criteria should aid in the differential diagnosis of invasive ductal adenocarcinoma from benign/reactive ducts in the pancreas.