Calcium is a second messenger responsible for regulating a wide range of cellular processes. It is normally presented as brief spikes even in non-excitable cells. The necessity of limiting the period of calcium stimulation to brief bursts may depend upon the fact that prolonged elevation of calcium can be toxic. It can act on endonucleases in the nucleus to trigger programmed cell death. It will be argued that non-lethal effects of elevated calcium can lead to a variety of pathological conditions including hypertension, atherosclerosis, transformation, malignant hyperthermia and possible neural disorders such as spreading depression and manic-depressive illness.