Multiple myeloma (MM) is a monoclonal malignant plasma cell disorder with an apparent homogeneity as opposed to leukemia and lymphomas. The recent introduction of thalidomide, lenalidomide and bortezomib has prolonged survival of patients with MM, and drug resistance or relapse of disease is perhaps still the major concern. Deregulation of hundreds of genes and multiple signaling pathways leads to MM pathogenesis and disease progression. While many of these genes and signaling pathways are regulated by microRNAs (miRNAs). miRNAs are small 19-22 nucleotide single-stranded RNAs that either as tumor suppressors or oncogenes play an important role in the progression and pathogenesis of cancer. Among them, microRNA-21 (miR-21) is frequently up-regulated in many cancers. Recent studies have shown that miR-21 displays an important role in the occurrence, development, recurrence and drug resistance of MM. In this review, we aim at summarizing the current knowledge of miR-21 functions in MM, with an emphasis on its laboratory research and clinical research in MM.