Calcium, the great signaler, is at the heart of proliferation, differentiation, and cancer. It figures prominently in the five signals that activate proliferatively quiescent normal cells and then trigger chromosome replication and mitosis. Calcium regulates intercellular communication through gap junctions and triggers the terminal differentiation programs of cells such as colon cells and keratinocytes. Calcium is also the killer in the programmed suicide mechanism (apoptosis) of differentiated senescent cells or functionally superfluous cells that is needed to maintain tissue homeostasis. The cancer cells emerging from the multistep carcinogenic process with inactivated or deleted tumor-suppressor genes and/or activated oncogenes are much less dependent than normal cells on external growth factors because they make and secrete their own factors. They also need much less external calcium to proliferate, and they no longer obey calcium signals to differentiate and ultimately die.