The intracellular calcium ions (Ca) act as second messenger to regulate gene transcription, cell proliferation, migration and death. Accumulating evidences have demonstrated that intracellular Cahomeostasis is altered in cancer cells and the alteration is involved in tumor initiation, angiogenesis, progression and metastasis. Targeting derailed Casignaling for cancer therapy has become an emerging research area. This review summarizes some important Cachannels, transporters and Ca-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 Cachannels/transporters or Ca-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 Casignaling in different cancer cells, and to search for novel therapies to cure these malignancies by targeting Cachannels or transporters.