MicroRNAs (miRNAs) are short, endogenous, non-coding RNA molecules that regulate expression of specific target genes. Aberrant expression of microRNAs (miRNAs) has been implicated in the development and progression of many cancers, including melanoma. However, the precise mechanistic role of many miRNAs in cancer remains unclear. We have investigated the functional role of miR-7-5p in melanoma, and demonstrate that its expression is reduced in metastatic melanoma-derived cell lines compared with primary melanoma cells, and that when ectopically expressed miR-7-5p significantly inhibits melanoma cell migration and invasion. In addition, we used microarray profiling studies to identify a number of novel miR-7-5p target genes in melanoma cells, such as insulin receptor substrate-2 (IRS-2), and using RNA interference (RNAi) we provide evidence that IRS-2 activates protein kinase B (Akt) and promotes melanoma cell migration. Thus, miR-7-5p may represent a novel tumor suppressor miRNA in melanoma, acting at least in part via its inhibition of IRS-2 expression and oncogenic Akt signaling. Modulating miR-7-5p expression may represent a novel treatment approach for metastatic melanoma.