Cancer stem cells (CSCs; also known as tumour initiating cells) are a small population of cancer cells that retain characteristics similar to those of normal stem cells. CSCs are known to be responsible for metastasis, drug resistance and cancer recurrence. The lineages assumed by stem cells during hematopoiesis can be identified by the pattern of protein markers present on the surface of cells at different stages of differentiation. CSC surface markers provide molecular targeted therapies for various cancers, using therapeutic antibodies specific for the CSC surface markers. Moreover, the potential role of these cells in differentiation, treatment resistance, relapse and metastasis suggests that elimination of these cells can be a novel approach for oral cancer therapy. The combination of surgery, chemotherapy and radiation therapy has managed in controlling the disease, but overall the five year survival rate is poor. Hence along with these treatment modalities, controlling CSCs can prevent recurrence and increases overall disease free survival rate.