Abstract The cancer stem cell (CSC) model states that heterogeneous tumor cell populations are organized in a hierarchical manner, with a small population of CSCs at the apex. These CSCs are capable of self-renewal and giving rise to other cancer cell populations, conceptually analogous to the function of normal adult stem cells present in almost all organs. However, there has been significant controversy regarding the existence and identification of CSCs. We argue that technical differences in experimentation and CSC assays, CSC niche-dependency and plasticity, and CSC heterogeneity itself may explain some of the differences observed.