Increased resistance to apoptosis represents a key oncogenic mechanism in chronic lymphocytic leukemia (CLL) that has been attributed to the upregulation of the anti-apoptotic B cell lymphoma 2 (Bcl-2) family members. Such an observation was associated with the development of molecules inhibiting Bcl-2 activity, and among them, BH3-mimetics represent a novel class of therapeutic compounds. In 2016, venetoclax became the first approved oral inhibitor of Bcl-2, and it has been used with success in patients with CLL who present with a 17p deletion or TP53 mutations and in those who have received at least one prior therapy. However, its mechanism for controlling relapses, and its optimal use in terms of duration and combinations with other drugs, remain unknown. Therefore, this review focuses on the mechanisms controlling apoptosis, CLL B cell strategies to prevent apoptosis including in response to BH3-mimetics, and arguments supporting the use of BH3-mimetics in association with other therapies in order to limit compensatory mechanisms.