Tissue-specific miRNAs play an important role in cell differentiation and are often deregulated in many human diseases, including cancer. Reexpressing such “micro-sheriff” miRNAs in a cell can deliver a dramatic impact, because miRNAs regulate a vast number of genes and pathways, including oncogenes and tumor suppressor genes. Tissue-specific tumor-suppressing miRNAs have the potential to promote the redifferentiation of tumor cells to their normal counterparts and solid malignancies to their original tissue types. The lung-specific miRNA pneumomiR-29, downregulated in non–small cell lung cancer (NSCLC), suppresses tumorigenicity by normalizing atypical patterns of methylation in non–small cell lung cancer cells (15). Taulli et al. now report in this issue of JCI that reexpression of myomiR-1/206 in RMS cells reduces oncogenic phenotypes and induces myogenic differentiation by downregulating cancer-associated genes and upregulating muscle-specific genes (12). Remarkably, introduction of striated muscle-specific myomiR-1 (downregulated in RMS) or brain-specific neuromiR-124 (downregulated in glioblastoma) into HeLa cells, a very well-characterized cervical carcinoma line, can shift the mRNA expression profile toward that of the tissue in which these miRNAs were originally enriched (3); this finding suggests that particularly powerful tissue-specific miRNAs may actually be able to drive virtually any cancer cell (shown here as a “generic tumor cell”) toward a specific differentiated state. Arrows on the right indicate the status of tissue-specific miRNA expression and the corresponding expression patterns of oncogenic genes and differentiation genes, which are opposing.