MicroRNAs play diverse roles in both normal and malignant stem cells. Focusing on miRs and/or miR â -s abundant in squamous cell carcinoma (SCC) stem cells, we engineer an efficient, strand-specific expression library, and apply functional genomics screening in mice to identify which of 169 cancer-associated miRs are key drivers in malignant progression. Not previously linked functionally to cancer, miR-21-was the second top hit, surfacing in >12% of tumours. miR-21-also correlates with poor prognosis in human SCCs and enhances tumour progression in xenografts. On deleting the miR-21 gene and rescuing each strand separately, we document the dual, but independent, oncogenicity of miR-21 and miR-21. A cohort of predicted miR-21-targets inversely correlate with miR-21-in SCCs. Of particular interest is Phactr4, which we show is a miR-21-target in SCCs, acting through the Rb/E2F cell cycle axis. Through in vivo physiological miR screens, our findings add an interesting twist to an increasingly important oncomiR locus.