Melanoma is a leading cause of mortality from skin cancer and has a poor prognosis. Despite rapid advances in the treatment of this tumor type, the efficacy of current chemo-/targeted-therapies is still limited owing to the lack of sufficient drug accumulation in the tumor tissue and development of chemo-resistance. Recently, the application of mesenchymal stem cells (MSCs) in cancer therapy has gained substantial attention, suggesting their potential roles as an intriguing vehicle in improving the delivery of targeted agents. MSCs are genetically modified with suicide tumor suppressor genes to inhibit cell signaling pathways associated with the progression and metastatic features of melanoma. Here we describe the clinical application of MSCs in melanoma with a particular emphasis on recent findings on the role of MSC expressing a distinct set of biologically functional chemokines and tumor suppressing agents. Accumulating data has shown the tumor- oriented homing capacity of MSCs and their applications as a vehicle (e.g., adipose derived mesenchymal stem cells expressing TRAIL, interferon-α/γ, pigment epithelium-derived factor and cytosine deaminase). Several questions regarding possible potential and intrinsic mechanisms that might induce tumorigenesis and drug resistance are yet to be addressed for tailoring MSC-nbased treatment of melanoma.