Tumors are composed by a heterogeneous population of cells. Among them, a sub-population of cells, termed cancer stem cells, exhibit stemness features, such as self-renewal capabilities, disposition to differentiate to a more proliferative state, and chemotherapy resistance, processes that are all mediated by Ca²⁺. Ca²⁺ homeostasis is vital for several physiological processes, and alterations in the patterns of expressions of the proteins and molecules that modulate it have recently become a cancer hallmark. Store-operated Ca²⁺ entry is a major mechanism for Ca²⁺ entry from the extracellular medium in non-excitable cells that leads to increases in the cytosolic Ca²⁺ concentration required for several processes, including cancer stem cell properties. Here, we focus on the participation of STIM, Orai, and TRPC proteins, the store-operated Ca²⁺ entry key components, in cancer stem cell biology and tumorigenesis.