Pancreatic cancer (PC) is a complex disease harboring a myriad of genetic and epigenetic changes. The dismal survival of patients diagnosed with PC is in part due to de novo and acquired resistance to conventional therapeutics, resulting from deregulated signaling including aberrant expression of small nc miRNAs. Emerging research in this area has lead to the identification and characterization of deregulated miRNAs, which have generated a renewed interest and hope in that novel targeting of miRNAs may lead to a better clinical outcome for patients diagnosed with PC. However, recent evidence suggests that miRNAs are also under a highly coordinated system of epigenetic regulation emphasizing the fact that the design of miRNAs as targeted therapy may not be as simple as originally anticipated. For a successful miRNA-based therapeutic regimen, a holistic integrated approach may be required to take into account because of these emerging epigenetic regulatory mechanisms. In this article, we will discuss miRNA epigenetics, it’s significance in PC and the use of a systems science to identify these aberrant epigenetically groomed miRNAs, and we believe that such knowledge would likely benefit further research to realize the dream of miRNA-based targeted therapy for human malignancies.