This review is aimed at exploring the literature on the clinical manifestation and role of cancer stem cells, specific markers which provide improved and accurate detection of cancer stem cells, the influence of chemotherapy and radiotherapy on cancer stem cells that develop in head and neck squamous cell carcinoma and its resistance to these therapies. Cancer stem cells are a subpopulation of tumor cells that possess the ability for self-renewal, self-reestablishment, and often exhibit resistance to existing treatment methods. Disruption of the communication between cancer stem cells and endothelial cells offers treatment advantages, specifically in treatment methods that eradicate the vessel system around the tumor to disrupt the tumor niche. Due to their great similarity with normal stem cells, it is very necessary to establish effective and accurate identification methods for cancer stem cells in order to support prognosis and treatment methods. The molecular markers such as CD44, ALDH and CD133 have been recognized as effective molecular markers for head and neck squamous cell carcinoma. These molecular markers provide improved and accurate detection and identification methods for the characterization of cancer stem cells and provide advantages in designing target therapies.