Cancer stem cells are found in many cancer types. They comprise a distinct subpopulation of cells within the tumor that exhibit properties of stem cells. They express a number of cell surface markers, such as CD133, CD44, ALDH, and EpCAM, as well as embryonic transcription factors Oct4, Nanog, and SOX2. CSCs are more resistant to conventional chemotherapy and can potentially drive tumor relapse. Therefore, it is essential to understand the molecular mechanisms that drive chemoresistance and to target them with specific therapy effectively. Highly conserved developmental signaling pathways such as Wnt, Hedgehog, and Notch are commonly reported to play a role in CSCs chemoresistance development. Studies show that particular pathway inhibitors combined with conventional therapy may re-establish sensitivity to the conventional therapy. Another significant contributor of chemoresistance is a specific tumor microenvironment. Surrounding stroma in the form of cancer-associated fibroblasts, macrophages, endothelial cells, and extracellular matrix components produce cytokines and other factors, thus creating a favorable environment and decreasing the cytotoxic effects of chemotherapy. Anti-stromal agents may potentially help to overcome these effects. Epigenetic changes and autophagy were also among the commonly reported mechanisms of chemoresistance. This review provides an overview of signaling pathway components involved in the development of chemoresistance of CSCs and gathers evidence from experimental studies in which CSCs can be re-sensitized to conventional chemotherapy agents across different cancer types. [ABSTRACT FROM AUTHOR]