OBJECTIVES/HYPOTHESIS: To determine if melanoma cells secrete chemotactic factors that result in the migration of multipotent stem cells. STUDY DESIGN: In vitro cell culture. METHODS: Chemotaxis and invasion of human mesenchymal stem cells (hMSCs) was determined using the modified Boyden chamber assay. Quantification of growth factors secreted by melanoma cells (A375) was determined using enzyme-linked immunosorbent assay. RESULTS: Conditioned A375 melanoma media caused significant migration and invasion of hMSCs compared to serum-free controls and conditioned media from normal melanocytes (P < .0001). The migratory effect appeared maximal after the A375 media was conditioned for 48 hours. Physiologically relevant concentrations of fibroblast growth factor-2 (FGF2) (90 pg/mL) secreted by A375 melanoma cells caused significant migration of hMSCs (P < .001) compared to serum-free and normal melanocyte controls. Neutralization of FGF2 inhibited the migration of hMSCs to that of the negative controls (conditioned media from normal melanocytes). CONCLUSIONS: The melanoma tumor microenvironment may be maintained through chemotaxis and invasion of multipotent hMSCs, and this migratory effect appears to be mediated in part through secretion of FGF2 by melanoma cells.