Ca(2+), the main second messenger, is central to the regulation of cellular growth. There is increasing evidence that cellular growth and proliferation are supported by a continuous store-operated Ca(2+) influx. By controlling store refilling, the sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) also controls store-operated calcium entry and, thus, cell growth. In this review, we discuss data showing the involvement of SERCA in the regulation of proliferation and hypertrophy. First, we describe the Ca(2+)-related signaling pathways involved in cell growth. Then, we present evidence that SERCA controls proliferation of differentiated cells and hypertrophic growth of cardiomyocytes, and discuss the role of SERCA isoforms. Last, we consider the potential therapeutic applications of increasing SERCA activity for the treatment of cardiovascular diseases and of modulating SERCA and SR content for the treatment of cancer.