Calcium homeostasis of the endoplasmic reticulum (ER) is involved in intracellular signaling pathways and is implicated in major cell functions such as cell growth, differentiation, protein synthesis and apoptosis. The accumulation of calcium in the ER is performed by specific sarco/endoplasmic reticulum calcium transport ATPases (SERCA iso-enzymes). The expression of biochemically distinct SERCA isoforms is cell type dependent and developmentally regulated. This review summarizes pertinent data about the modulation of the expression of SERCA enzymes during the differentiation of normal and tumor cells. These data support the implication of SERCA pumps and especially SERCA3 in the differentiation program of cancer and leukemia cells. During the multi-step process of colon carcinogenesis, the decrease of SERCA3 expression seems to be linked to enhanced APC/ss-catenin/TCF4 signaling and deficient Sp1-like factor-dependent transcription.