The limited success seen in cancer immunotherapy signifies that an alternative approach is required. Advances in cancer biology have identified a biologically unique subpopulation of cells, termed cancer stem cells (CSC), that survive after conventional therapy. CSCs are the putative cancer-initiating cells responsible for tumor initiation, progression and metastasis. CSCs might be able to evade the immune system by generating a tolerogenic response facilitated by the immunosuppressive factor CD200. This article reviews the biological importance of CSCs and the potentially important role of CD200 in tumor immunology. Moreover, we discuss the prospective role CD200 plays in the ability of a CSC to escape the immune system. Future immunotherapy must consider targeting CSCs to achieve curative responses.