BCL-2 was isolated from the t(14;18) chromosomal breakpoint in follicular B-cell lymphoma(1-3). Bcl-2 has the unique oncogenic role of extending cell survival by inhibiting a variety of apoptotic deaths(4-13). An emerging family of Bcl-2 -related proteins share two highly conserved regions(14-20) referred to here as Bcl-2 homology 1 and 2 (BH1 and BH2) domains (Fig. 1). This includes Bax which heterodimerizes with Bcl-2 and when overexpressed counteracts Bcl-2(14). We report here that site-specific mutagenesis of Bcl-2 establishes the two domains as novel dimerization motifs. Substitution of Gly 145 in BH1 domain or Trp 188 in BH2 domain completely abrogated Bcl-2’s death-repressor activity in interleukin-3 deprivation, gamma-irradiation and glucocorticoid-induced apoptosis. Mutations that affected Bcl-2’s function also disrupted its heterodimerization with Bax, yet still permitted Bcl-2 homodimerization. These results establish a functional role for the BH1 and BH2 domains and suggest Bcl-2 exerts its action through heterodimerization with Bax.