Resistance to anticancer agents is the major clinical obstacle to the successful treatment of cancer, yet the mechanisms underlying drug resistance have not been fully characterized. MicroRNAs (miRNAs) are endogenous, small (19-25 nucleotides in length) noncoding RNAs, which function by base pairing with messenger RNAs, thereby regulating protein expression. Emerging evidence shows that alteration of miRNAs is involved in cancer initiation and progression. MiR-21 is a miRNA that is overexpressed in most tumor types, and acts as an oncogene by targeting many tumor suppressor genes related to proliferation, apoptosis, and invasion. In vivo and in vitro studies suggest that miR-21 may serve as a diagnostic and prognostic marker for human malignancies. More recently, studies have identified an important role for miR-21 in anticancer drug resistance. Here, we review the mechanisms underlying miR-21-mediated chemoresistance and the potential use of miR-21 as a novel molecular target for cancer chemotherapy.