Research conducted over the past two decades has provided convincing evidence that cell death, and more specifically apoptosis, can exceed single cell boundaries and can be strongly influenced by intercellular communication networks. We recently reported that gap junctions (i.e. channels directly connecting the cytoplasm of neighboring cells) composed of connexin43 or connexin26 provide a direct pathway to promote and expand cell death, and that inositol 1,4,5-trisphosphate (IP(3)) diffusion via these channels is crucial to provoke apoptosis in adjacent healthy cells. However, IP(3) itself is not sufficient to induce cell death and additional factors appear to be necessary to create conditions in which IP(3) will exert proapoptotic effects. Although IP(3)-evoked Ca(2+) signaling is known to be required for normal cell survival, it is also actively involved in apoptosis induction and progression. As such, it is evident that an accurate fine-tuning of this signaling mechanism is crucial for normal cell physiology, while a malfunction can lead to cell death. Here, we review the role of IP(3) as an intracellular and intercellular cell death messenger, focusing on the endoplasmic reticulum-mitochondrial synapse, followed by a discussion of plausible elements that can convert IP(3) from a physiological molecule to a killer substance. Finally, we highlight several pathological conditions in which anomalous intercellular IP(3)/Ca(2+) signaling might play a role.