The frequency of detection of cystic pancreatic lesions with cross-sectional imaging, particularly with multidetector computed tomography, magnetic resonance (MR) imaging, and MR cholangiopancreatography, is increasing, and many of these cystic pancreatic lesions are being detected incidentally in asymptomatic patients. Because there is considerable overlap in the cross-sectional imaging findings of cystic pancreatic lesions, and because many of these lesions being detected are smaller than 3 cm in diameter and lack any specific cross-sectional imaging features, it has become difficult to make informed decisions about patient management when the precise diagnosis remains uncertain. This article presents the limitations of cross-sectional imaging in patients with cystic pancreatic lesions, details advances in knowledge of the genomic and epigenomic changes that lead to progression of carcinogenesis, outlines the current understanding of the natural history of mucinous cystic lesions, and includes the current use and future potential of novel tumor markers and molecular analysis to characterize cystic pancreatic lesions more precisely. The need to move beyond cross-sectional imaging morphology and toward the use of new techniques to diagnose these lesions accurately is emphasized. An algorithm that uses these techniques is proposed and will hopefully lead to improved patient management. © RSNA, 2014 Online supplemental material is available for this article.