Recent studies have highlighted the importance of the secretory pathway in stress-induced apoptotic signaling. Sensing stress at the endoplasmic reticulum and Golgi might first trigger recovery mechanisms, followed by apoptosis if repair is unsuccessful. Cleavage of endoplasmic-reticulum- or Golgi-resident proteins can signal repair or apoptosis and promote organelle disassembly during apoptosis. Initiation of apoptosis from the secretory pathway requires components of the death machinery localized to these membranes. Extensive trafficking between compartments of the secretory pathway might allow the cell to integrate signals and to determine the proper response to a particular stress.