Following the first small non-coding RNA identification in 1993, accumulated knowledge on the biogenesis, homeostasis and functional roles of microRNAs in different physiological and pathophysiological conditions has been discovered. MicroRNAs act through epigenetic regulation of gene expression. MiR-34a is a member of the MiR-34 family that is involved in p53 pathways, and is implicated in cell death/survival signaling. MiR-34a is associated with G1 cell cycle arrest, senescence and apoptosis, thereby possessing a tumor suppressor activity. Deregulation of MiR-34a has been reported in several types of cancers. MiR-34a downregulation has been correlated with cancer multidrug resistance (MDR), which is a major challenge for successful cancer chemotherapy. MiR-34a mimetic agents have been shown to attenuate drug resistance in different cancer cell lines. This review focuses on the in vitro, experimental and clinical findings dealing with the role of miR-34a downregulation in MDR, and potential therapeutic opportunities arising from this role of miR-34a.