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MicroRNAs (miRNAs) are important regulators of distinct biological processes and are tightly related with several diseases, including cancer. In the last years, miRNAs have been shown to play an important role in drug resistance/ sensitivity to anticancer drugs. This chapter first addresses the phenomenon of drug resistance in cancer cells. It then describes the role of miRNAs in drug resistance or drug sensitivity, including a review of the role of miRNAs and their validated targets in cancer drug resistance. Furthermore, it focuses on miRNAs that target cellular proteins related to drug resistance such as p53 or proteins involved in cellular processes such as apoptosis, autophagy, DNA damage response, epithelial to mesenchymal transition and cancer stem cell phenotype, drug efflux or drug metabolism. In addition, the non-genetic acquisition of drug resistance through the transfer of miRNAs from drug resistant to drug sensitive cells via microvesicles or exosomes is also discussed. Finally, the known miRNA polymorphisms associated with drug resistance are addressed. © Springer International Publishing Switzerland 2014. All rights are reserved.