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Proteins synthesized in the cytosol can be inserted into or across organellar membranes depending on the signals present in their primary sequences. Proteins of the Bcl-2 family, which includes proteins that promote programmed cell death (apoptosis) and proteins that inhibit apoptosis, have signals that can target particular members to either the mitochondria or the endoplasmic reticulum (ER) or both. Germain and Shore discuss evidence for a role for the anti-apoptotic members of the family at the ER and describe an interaction with the FK506 binding protein, FKBP38, that may regulate the relative distribution of Bcl-2 proteins at the ER or mitochondria. This interaction may control the cell's sensitivity to apoptotic stimuli.