With the cementing of the cancer stem cell (CSC) concept, cancer biology and cancer drug discovery have attained a new avenue to target cancer. Studying the hierarchy of tumor tissue organization and how to inhibit the cell that resides at the very top of this hierarchy has opened up a new branch of tumor biology and given the opportunity to develop novel cancer-targeting strategies. With the discovery of CSCs in majority of cancer indications there seems to be a universal applicability of the concept. However, the CSC field is still at an early fledgling state and a lot more needs to be done in terms of understanding their emergence, maintenance, role in metastasis and their function in shaping the tumor architecture. CSCs are considered to be responsible for tumor initiation, metastasis and resistance to conventional radio and chemotherapy. Therefore, different approaches to targeting these tumorigenic and rare cells are urgently needed in order to improve the efficacy of anti-cancer therapy. We outline here the cancer stem cell concept and its relevance as well as biotherapeutic approaches to CSC targeting, including oncolytic viruses, monoclonal antibodies, cytokines and cytotoxic T lymphocytes.