The cancer stem cell concept assumes that cancers are mainly sustained by a small pool of neoplastic cells, known as cancer stem cells or tumor initiating cells, which are able to reproduce themselves and produce phenotypically heterogeneous cells with lesser tumorigenic potential. Cancer stem cells represent an appealing target for development of more selective and efficient therapies. However, direct testing of the cancer stem cell concept and assessment of its therapeutic implications in human cancers have been complicated by the use of immunocompromised mice. Genetically defined immunocompetent autochthonous mouse models of human cancer provide a valuable tool to address this problem. Furthermore, they allow for a better understanding of the relevance of mechanisms controlling normal stem cell compartment to carcinogenesis. Advantages and disadvantages of some of the existing mouse models are reviewed, and future challenges in cancer stem cell research are outlined.