MicroRNA (miRNA) dysregulation in pancreatic ductal adenocarcinoma (PDA) has been reported but not previously profiled during PDA tumorigenesis. Chu and colleagues (in a study beginning on page 569) identified miRNA-21 (miR-21) overexpression in pre-malignant and PDA lesions and demonstrated regulation of pro-tumorigenic effector pathways including MAPK, mTOR and actin cytoskeleton pathways downstream of mutant KRAS. Early systemic miR-21 inhibition in vivo completely intercepted premalignant progression in the early pancreatic intraepithelial neoplasia (PanIN) stage. The cover art demonstrates miRNA-21 expression in PDA using a fluorescence in situ hybridization assay. Expression of miR-21 is concentrated in ductal epithelial cells and becomes increasingly expressed with neoplastic progression from PanINs to PDA (miR-21 expression in epithelial ducts in green and DAPI in the nucleus in blue). miR-21 may be useful for identifying and intercepting developing PDA and other KRAS-driven cancers.