The programmed suicide of cells (apoptosis) is essential for embryonic development, tissue homeostasis and cancer prevention. Many anti-cancer treatments kill tumour cells by activating the intrinsic apoptotic pathway regulated by the BCL-2 family. The development of drugs that mimic BH3-only protein action by binding and inhibiting pro-survival BCL-2 family members has provided the opportunity for targeted therapy by direct triggering of the intrinsic apoptotic pathway. ABT-263 is a recently developed BH3 mimetic currently in clinical trial, which potently inactivates BCL-2, BCL-XL and BCL-W but not MCL-1 or BCL2A1. The efficacy and specificity of ABT-263 raises the possibility of targeting specific pro-survival family members most critical for the survival of a particular cancer, thereby reducing cytotoxicity to normal cells. We are using conditional knock-out mouse models to investigate the requirements of pro-survival BCL-2 family members, Bcl-2, Bcl-xL and Mcl-1, in normal cells and tissues to study and predict the potential toxicity induced by their therapeutic inhibition.