Pancreatic cancer is a highly aggressive malignancy. This feature is believed to be partly attributable to the chemotherapy-resistant characteristics of specific subgroups of pancreatic cancer cells, namely those with an epithelial-mesenchymal transition (EMT) phenotype and cancer stem cells. Accumulating evidence suggests that several new and emerging concepts might be important in the drug-resistant phenotype of these cell types. An understanding of the molecular mechanisms underlying drug resistance in patients with pancreatic cancer might help researchers to devise novel strategies to overcome such resistance. In particular, microRNAs (miRNAs) seem to be critical regulators of drug resistance in pancreatic cancer cells. Selective and targeted elimination of cells with an EMT phenotype and cancer stem cells could be achieved by regulating the expression of specific miRNAs.