Ca2+ ions are key second messengers in both excitable and non-excitable cells. Owing to the rather pleiotropic nature of Ca2+ transporters and other Ca2+-binding proteins, however, Ca2+ signaling has attracted limited attention as a potential target of anticancer therapy. Here, we discuss cancer-associated alterations of Ca2+ fluxes at specific organelles as we identify novel candidates for the development of drugs that selectively target Ca2+ signaling in malignant cells.