MicroRNAs (miRNA) are short, single-stranded, noncoding RNAs that regulate a number of cellular processes through their capability to silence the expression of target proteins. Using miRNAs to target and reduce the expression of tyrosinase, the key enzyme involved in the synthesis of skin pigment melanin, presents a novel and feasible approach for achieving skin whitening. We have developed an artificial miRNA expression system that synthesizes miRNAs that downregulate tyrosinase expression by binding and degrading tyrosinase messenger RNAs. We used this anti-tyrosinase miRNA expression system (miR-Tyro) to successfully demonstrate the feasibility of miRNA-mediated skin whitening in vitro and in vivo. In light of bans of previously proven and popular skin whitening cosmetic ingredients such as hydroquinone and kojic acid, use of miRNAs that target and silence tyrosinase expression may present a novel and promising cosmetic approach to achieve skin whitening. Our finding on mirTyro-mediated skin whitening in mice is the first miRNA application proven to be feasible in vivo.