All six human pro-survival Bcl-2 proteins can drive cancer development and contribute to therapy resistance. However, their relative abilities to protect cells against cancer therapy were not examined previously. We report that Bcl-2, Bcl-xL or Bcl-w consistently protected leukemic cells better than Bcl-B, Bfl-1 or Mcl-1, against a wide variety of anti-cancer regimens. Current thinking would attribute this to differences in their ability to bind to BH3-only proteins, Bax and Bak. To address this, we established the first complete, quantitative cellular interaction profile of all human pro-survival Bcl-2 proteins with all their pro-apoptotic relatives. Binding was unexpectedly promiscuous, except for Bad and Noxa, and did not explain the differential anti-apoptotic capacity of the Bcl-2 proteins. Rather, Bcl-B, Bfl-1 or Mcl-1 proved less potent due to steady state- or drug-induced proteasomal degradation. All six Bcl-2 proteins similarly protected against the diverse anti-cancer regimens when expressed at equal protein levels, in agreement with their broad interaction profile. Therefore, clinical diagnostics should include all family members and should be performed at the protein rather than at the mRNA level. In drug development, targeting the ubiquitination machinery of pro-survival Bcl-2 proteins will complement and potentially improve on targeting Bcl-2 protein interactions with BH3 mimetics.