The human population is increasingly facing various diseases, including types of cancer, that cannot be cured with conventional drugs. Advanced drug targeting of tumor cells is also often impossible when treating highly invasive and infiltrative tumors such as glioblastoma or pulmonary cancer, because of tumor cells' high migration and invasiveness. Pluripotent human mesenchymal stem cells (hMSCs) have been extensively studied, and strategies are being proposed for treating “incurable” cancers and injury/disease-affected organs. Because of their own intrinsic properties, involving homing and immunomodulatory potency, hMSCs could be used as an excellent cell/drug delivery vehicle in those cell-based therapies. Their unprecedented use has been shadowed, however, by their spontaneous transformation, which links them to cancer-initiating cells during tumor development. How malignant initiation proceeds in vivo, and what are the exact characteristics of the cancer-initiating cells, still remain to be investigated. In the present review, the authors summed up the most recent knowledge about hMSC characteristics, their malignant transformation, and outlined the possibilities of their safe use in novel cell-based therapies. Cancer 2010. © 2010 American Cancer Society.