Zhang, Ge and Fuchs have provided new insights into the role of microRNA-125b (miR-125b) in the initiation, progression and maintenance of squamous cell carcinoma (SCC). Using an inducible mouse model, they found that miR-125b overexpression in skin epithelium promoted spontaneous tumour formation as well as sensitizing skin to chemically-induced carcinogenesis. Furthermore, miR-125b expression maintained tumour growth by repressing differentiation and promoting a cancer stem-cell-like transcriptional programme. By identifying and validating miR-125b targets specifically associated with tumorigenesis, they found that miR-125b directly represses stress-responsive MAPK transcripts. It also indirectly maintains epidermal growth factor receptor (EGFR) signalling, by repressing vacuolar protein-sorting 4 homologue B (Vps4b), which encodes a protein that promotes endocytic degradation of phosphorylated EGFR.