Changes in the cytoplasmic calcium concentration ([Ca(2+)](i)) regulate a wide variety of cellular processes. Here we demonstrate that increased [Ca(2+)](i) was able to induce hormone-independent survival and proliferation, as well as to evoke apoptosis in human myelo-erythroid GM-CSF/IL-3 dependent leukemia cells (TF-1). Cellular responses induced by elevated [Ca(2+)](i) depended on the duration and amplitude of the calcium-signal. Moderate or high, but transient, elevation of [Ca(2+)](i) caused a transient, biphasic activation of ERK1/2 and protected cells from hormone withdrawal-induced apoptosis.(1) In contrast, high and long-lasting elevation of [Ca(2+)](i) led to sustained activation of the ERK1/2 kinases and apoptosis of TF-1 cells. Our data suggest that a time-dependent action of the MAPK pathway works as a decision-point between cell proliferation and apoptosis.