The intracellular calcium ions (Ca²⁺) act as second messenger to regulate gene transcription, cell proliferation, migration and death. Accumulating evidences have demonstrated that intracellular Ca²⁺ homeostasis is altered in cancer cells and the alteration is involved in tumor initiation, angiogenesis, progression and metastasis. Targeting derailed Ca²⁺ signaling for cancer therapy has become an emerging research area. This review summarizes some important Ca²⁺ channels, transporters and Ca²⁺-ATPases, which have been reported to be altered in human cancer patients. It discusses the current research effort toward evaluation of the blockers, inhibitors or regulators for Ca²⁺ channels/transporters or Ca²⁺-ATPase pumps as anti-cancer drugs. This review is also aimed to stimulate interest in, and support for research into the understanding of cellular mechanisms underlying the regulation of Ca²⁺ signaling in different cancer cells, and to search for novel therapies to cure these malignancies by targeting Ca²⁺ channels or transporters.