Despite recent progresses in tumor therapy and increased knowledge in tumor biology, tumor remains a common and lethal disease worldwide. Cancer stem cells (CSCs) are a subset of cancer cells with a stem cell-like ability, which may drive tumor growth and recurrence and are resistant to many current anticancer treatments. Solid tumors are regarded as "organs" which are comprised of cancer cells and the tumor stroma. The tumor microenvironment makes up the stroma of the tumor, which occupies the majority of the tumor mass, including the extracellular matrix (ECM), mesenchymal stem cells (MSCs), endothelial cells, immune cells, and, what is more, networks of cytokines and growth factors. The microenvironment or niche surrounding CSCs largely governs their cellular fate. Recent work has revealed that the microenvironment supports CSC self-renewal and simultaneously serves as a physical barrier to drug delivery. The tumor microenvironment plays pivotal roles in each stage of tumor development. Knowledge about the interactions of CSCs with their microenvironment would seem to be of most importance for developing new treatment strategies.