Tumor cells need to disrupt apoptosis pathways to escape the cytotoxic action of oncogene activation and microenvironmental stress during the carcinogenic process. However, the cytotoxic action of classical chemotherapy, and radiotherapy includes the induction of apoptotic cell death. Therefore, apoptosis resistance of tumor cells contributes to the failure of chemotherapy and radiotherapy. During the last two decades, extensive research aimed at an improved understanding of the complex signaling pathways that control apoptosis execution in normal cells and of the endogenous factors that mediate apoptosis resistance of cancer cells. Among these, the Bcl-2 protein family attracted major attention for the development of compounds that specifically target apoptosis resistance of cancer cells. Bcl-2 proteins are master regulators of the intrinsic apoptosis pathway that is crucial for apoptosis execution in response to DNA-damage. The review will highlight current knowledge on the regulation of apoptosis pathways and discuss several approaches that target the Bcl-2 rheostat to counteract tumor cell intrinsic apoptosis resistance that may therefore be of value for a biological modulation of apoptosis resistance.