Apoptosis is an essential biological process involved in tissue homeostasis and immunity. Aberrations of the two main apoptotic pathways, extrinsic and intrinsic, have been identified in hematological malignancies; many of these aberrations are associated with pathogenesis, prognosis and resistance to standard chemotherapeutic agents. Targeting components of the apoptotic pathways, especially the chief regulatory BCL-2 family in the intrinsic pathway, has proved to be a promising therapeutic approach for patients with hematological malignances, with the expectation of enhanced efficacy and reduced adverse events. Continuous investigations regarding the biological importance of each of the BCL-2 family components and the clinical rationale to achieve optimal therapeutic outcomes, using either monotherapy or in combination with other targeted agents, have generated inspiring progress in the field. Genomic, epigenomic and biological analyses including BH3 profiling facilitate effective evaluation of treatment response, cancer recurrence and drug resistance. In this review, we summarize the biological features of each of the components in the BCL-2 apoptotic pathways, analyze the regulatory mechanisms and the pivotal roles of BCL-2 family members in the pathogenesis of major types of hematologic malignances, and evaluate the potential of apoptosis- and BCL-2-targeted strategies as effective approaches in anti-cancer therapies.