Screening strategies of therapeutic molecules and targets have received increasing attention during the past few years. Indeed, identification of novel compounds and drug targets involved in apoptosis control is a major rate-limiting step in anticancer drug development efforts. In this review, we discuss the current screening methodologies to discover novel potential therapeutics targets and drugs implicated in the apoptotic pathway, in particular the intrinsic pathway. In addition, we present a proteomic screening strategy that led us to identify a mitochondrial glutathione-S-transferase as a novel regulator of the pro-apoptotic adenine nucleotide translocase pore function.