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MicroRNA‐221 (miR‐221) is one of the most frequently and consistently up‐regulated microRNAs (miRNAs) in human cancer. It has been hypothesized that miR‐221 may act as a tumor promoter. To demonstrate this, we developed a transgenic (TG) mouse model that exhibits an inappropriate overexpression of miR‐221 in the liver. Immunoblotting and immunostaining confirmed a concomitant down‐regulation of miR‐221 target proteins. This TG model is characterized by the emergence of spontaneous nodular liver lesions in approximately 50% of male mice and by a strong acceleration of tumor development in 100% of mice treated with diethylnitrosamine. Similarly to human hepatocellular carcinoma, tumors are characterized by a further increase in miR‐221 expression and a concomitant inhibition of its target protein‐coding genes (i.e., cyclin‐dependent kinase inhibitor [Cdkn]1b/p27, Cdkn1c/p57, and B‐cell …