Calcium is a ubiquitous second messenger and is involved in virtually all cellular functions. Cellular events being regulated by calcium include gene transcription, metabolism, proliferation and apoptosis. Cancer growth is based on increased proliferation, decreased differentiation and decreased apoptosis. Therefore, the intracellular Ca2+-homeostasis has become one of the focuses in current cancer research. Elevation of the cytoplasmic Ca2+-concentration can result from Ca2+-influx from the extracellular space or from Ca2+-release from intracellular stores. The main intracellular Ca2+-store is the endoplasmic reticulum (ER). The Ca2+-content of the ER is maintained by trans-membrane proteins involving the sarco/endoplasmic reticulum Ca2+-ATPase and the inositol-1,4,5-phosphat receptor. In this review, we summarize the current knowledge of the ER and its trans-membrane proteins as regulating structures of the intracellular Ca2+- homeostasis, what changes occur in malignant cells and how this promotes cancer. We further review possible pharmacological intervention and show future perspectives of the intracellular Ca2+-homeostasis as an anti-cancer target.