The recurrence and/or lack of response of certain tumors to radio- and chemotherapy has been attributed to a small subpopulation of cells termed cancer stem cells (CSCs). CSCs have been identified in many tumors (including solid and hematological tumors). CSCs are characterized by their capacity for self-renewal, their ability to introduce heterogeneity within a tumor mass and its metastases, genomic instability, and their insensitivity to both radiation and chemotherapy. The latter highlights the clinical importance of studying this subpopulation since their resistance to traditional treatments may lead to metastatic disease and/or tumor relapse. Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common malignancy worldwide with the highest incidence occurring in East Asia and eastern and southern Africa. Several cellular subpopulations believed to have CSC properties have been isolated from HNSCCs, but at present, identification and characterization of CSCs remains an experimental challenge with no established or standardized protocols in place to confirm their identity. In this review we discuss current approaches to the study of CSCs with a focus on HNSCCs, particularly in the context of what this might mean from a therapeutic perspective.