Calcium (Ca(2+)) is used as a signaling molecule to regulate many cellular processes. Calcium signaling generally involves transient elevations of the concentration of free Ca(2+) in the cytosol. More pronounced and sustained elevations of intracellular Ca(2+) concentrations are observed during apoptosis (programmed cell death). These Ca(2+) elevations have been shown to lead to the activation of proteases (calpains) and to changes in protein phosphorylation. Recent evidence, using chemical biology, has raised the possibility that calcium signaling is involved in sustained JNK activation during late phases of apoptosis. For at least some stimuli, calcium release leads to activation of calmodulin kinase II (CaMKII), apoptosis signaling kinase 1 (ASK1) and JNK. Calcium signaling may help to orchestrate the apoptotic response during the execution phase.