The Rab GTPase family of trafficking proteins is being increasingly implicated in cancer cell biology. Genetic screens have identified Rab27a as a gene involved in melanoma progression. However, while the role of Rab27a in melanosome trafficking in melanocytes is well known, its precise function in melanoma cells remains poorly understood. In the present study, we found that Rab27a expression was significantly increased in human melanoma samples compared to benign nevi. Rab27a was also highly expressed in many melanoma cell lines. Knockdown of Rab27a gene expression in melanoma cell lines inhibited proliferation and invasion in a 3D spheroid assay. This decrease in invasion was accompanied by a loss of invadopodia activity. In addition, besides melanosomes, exogenously expressed Rab27a-GFP also partially co-localized with Matrix metalloproteinase-14 (MMP14), which is involved in invadopodia-meditated matrix degradation. Treatment of melanoma cells with simvastatin, a non-specific inhibitor of GTPases, inhibited invasion at low concentrations, while high concentrations caused cell death. Invasion was more substantially inhibited in Rab27a-high cell lines, suggesting inhibition of Rab27a may partially explain the effect of statins on melanoma invasion. Our data indicate that Rab27a plays a central role in proliferation and invasion in Rab27a-high melanoma cells, although the molecular mechanisms underlying the effect on proliferation are still unclear. Rab27a expression is confined to melanocytic cells as well as some other specialized cell types, making Rab27a a novel potential therapeutic target.