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Significant advances have been made in the treatment of melanoma by targeting key cellular pathways, but additional targets are needed as many patients do not respond or relapse with resistant disease. MicroRNA-155 (MiR-155) has previously been shown to regulate melanoma cell growth and acts as a tumor suppressor. We tested a clinical population of melanoma tumors for miR-155 expression, and find that expression is low in most patients, although not predictive of outcome. We identified the protein kinase WEE1 as a novel target of miR-155. A mouse model of experimental metastasis finds that both increased expression of miR-155 and silencing of WEE1 lead to decreased metastases. Loss of miR-155 and increased expression of WEE1 may contribute to the metastatic phenotype in patients with melanoma.