MicroRNAs (miRNAs) are small noncoding RNAs of 19-25 nt that can regulate gene expression at a posttranscriptional level. Increasing evidence indicates that miRNAs participate in almost every step of cellular processes and are often aberrantly expressed in human cancer. miR-221 and miR-222 are two highly homologous miRNAs that always act as a gene cluster (miR-221/222) in cellular regulation and have extensively been studied in cancer network. Here, we review the role of miR-221/222 in breast cancer (BCa) development and progression: regulating proliferative signaling pathways, altering telomere and telomerase activity, avoiding cell death from tumor suppressors, autophagy and apoptosis, monitoring angiogenesis, supporting epithelial-mesenchymal transition, and even controlling cell-specific function within microenvironment. We consider that miR-221/222 act as promising biomarkers for BCa and they would offer a new way in molecular targeting cancer treatment.