MicroRNAs are small non-coding RNAs of 18-25 nucleotides that regulate gene expression at the post-transcriptional level through binding to the 3´-UTR of mRNAs and block mRNA transcription or regulate its resistance. Increasing evidence indicates that dysregulation of miRNA is a hallmark of cancer. The miRNAs have an essential role in the regulation of oncogenes or tumor suppressor genes in cell signaling pathways. MiR-221 and miR-222 are two homologous microRNAs, the high expression levels of which have been commonly demonstrated in multiple human cancer types. The miR-221/miR-222 functions have been verified as oncogenes or tumor suppressors. Here, we reviewed the roles of miR-221/miR-222 in various kinds of cancer progression and development: controlling proliferative signaling pathways, avoiding cell deaths resulted from tumor suppressors, monitoring angiogenesis and even supporting epithelial-mesenchymal transition. We discussed that miR-221/miR-222 act as promising biomarkers for detection of human cancer types and suggested a new pathway for molecular targeted cancer therapy.