Pancreatic adenocarcinoma and hepatocellular carcinoma are devastating human malignancies that are characterized by poor prognosis, late onset, and a lack of known biomarkers. New diagnostic and therapeutic molecular targets are desperately needed to develop novel and effective treatment strategies. MicroRNAs (miRNAs) are an emerging class of molecules with roles in various cellular processes, including growth, survival, and apoptosis. Most importantly, aberrant expression of miRNAs has been implicated in cancer pathogenesis. miRNA expression profiles of pancreatic adenocarcinoma and hepatocellular carcinoma indicate selective overexpression of oncogenic miRNAs and down-regulation of tumor suppressive miRNAs in these cancers. This review summarizes results from key studies conducted to characterize the miRNA expression profiles of pancreatic adenocarcinoma and hepatocellular carcinoma and describes the potential mechanisms by which some oncogenic or tumor suppressive miRNAs act. Furthermore, this review outlines novel therapeutic strategies for targeting miRNAs.