Mitochondria receive calcium (Ca2+) signals from endoplasmic reticulum (ER) and decode them into pro-apoptotic inputs, which lead to cell death. Therefore, mitochondrial Ca2+ overload is considered a fundamental trigger of the apoptotic process, and several oncogenes and tumor suppressors modify the activity of protein involved in Ca2+ homeostasis to control apoptosis. The identification of the channel responsible for mitochondrial Ca2+ entry, the Mitochondrial Ca2+Uniporter (MCU), together with its regulatory components, MICU1 and MCUR1, provides new molecular tools to investigate this process. Recent data have also shown that miR-25 decreases mitochondrial Ca2+ uptake through selective MCU downregulation, conferring resistance to apoptotic challenges. MCU appears to be downregulated in human colon cancer samples, and accordingly, miR-25 is aberrantly expressed, indicating the importance of mitochondrial Ca2+ regulation in cancer cell survival.