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Bid, a pro-apoptotic member of the Bcl-2 family, was initially discovered through binding to both pro-apoptotic Bax and anti-apoptotic Bcl-2. During apoptosis, Bid can be cleaved not only by caspase-8 during death receptor apoptotic signaling, but also by other caspases, granzyme B, calpains and cathepsins. Protease-cleaved Bid migrates to mitochondria where it induces permeabilization of the outer mitochondrial membrane that is dependent on the pro-apoptotic proteins Bax and/or Bak, and thus Bid acts as a sentinel for protease-mediated death signals. Although sequence analysis suggests that Bid belongs to the BH3-only subgroup of the Bcl-2 family, structural and phylogenetic analysis suggests that Bid may be more related to multi-BH region proteins such as pro-apoptotic Bax. Analysis of membrane binding by protease-cleaved Bid reveals mechanistic similarities with the membrane binding of Bax. For both proteins, membrane binding is characterized by relief of N-terminal inhibition of sequences promoting migration to membranes, insertion into the bilayer of the central hydrophobic hairpin helices and exposure of the BH3 region. These findings implicate Bid as a BH3-only protein that is both structurally and functionally related to multi-BH region Bcl-2 family proteins such as Bax.