The endoplasmic reticulum (ER) plays a pivotal role in the folding and processing of newly synthesized proteins, reactions which are strictly calcium-dependent. Depletion of ER calcium pools activates a stress response (suppression of global protein synthesis and activation of stress gene expression) which is almost identical to that induced by transient ischemia or other forms of severe cellular stress, implying common underlying mechanisms. We conclude that disturbance of the ER functions may be involved in stress-induced cell injury. In our view, ER calcium homeostasis plays an important role in maintaining the physiological state in cells balanced between the extremes of growth arrest and cell death on the one hand, and uncontrolled proliferation on the other.