Cancer stem cells (CSCs) or tumor-initiating cells (TICs) represent a minority population of cells in a tumor that can self-renew and re-create the heterogeneity of the entire tumor. Cell lines, patient-derived tumor cells, and patient-derived xenografts have all been used to isolate presumptive CSC populations from different tumor types. Because of their purported roles in tumor recurrence and prognosis, numerous efforts have centered around reliably identifying CSCs using cell surface markers, and in using genomics tools to identify molecular features unique to these cells. In this brief review, we will discuss different markers, CD44, ALDH1, CD271 and others that have used for identifying and isolating CSCs from primary head & neck and oral squamous cell carcinomas. In particular, we focus on the challenges associated with these experiments as this will be useful to researchers attempting similar isolations. We also discuss some important molecular features gleaned from studying these CSCs such as the expression of stem cell-related markers, loss of cell adhesion and terminal differentiation markers, and the presence of both epithelial and epithelial-to-mesenchymal transition (EMT) features.