Cancer stem cells are a rare sub-population of cancer cells, responsible for metastasis, multiple differentiation, and tumor reoccurrence. These are one of the major reasons for the ineffectiveness of traditional cancer therapy, resulting in a relapse of many cancers. The current book chapter explores and characterizes immunological features of cancer stem cells and delves upon their significance for developing immunotherapy. We summarize: (1) characterization of cancer stem cells with comparison to general stem cells on the basis of molecular and specific CSC markers; (2) signaling pathways involved in therapy resistance of CSCs; (3) CSC niche and its contribution to tumor therapy; and (4) immunological response and comparison of current cancer stem cell-based immunotherapy. A detailed overview and better understanding of cancer stem cells and its correlation with immune system would provide a better insight for development of cancer stem cell-based immunotherapy.