AbstractDespite their profoundly different cellular composition, size, and function, megakaryocytes and platelets both depend on restraint of the intrinsic (or “mitochondrial”) apoptosis pathway by BCL-2 family prosurvival proteins for their development and viability. Activation of the pathway contributes to the clearance of megakaryocytes following platelet shedding and constrains platelet lifespan in the circulation. Important questions remain as to how apoptosis is initiated in these cells at steady state and in response to pathophysiological insults.