Abstract Over the last decade, the advent of Bruton tyrosine kinase inhibitors (BTKi) has profoundly modified the therapeutic strategy in chronic lymphocytic leukemia (CLL), introducing the concept of treatment until progression. Initially, the bcl-2 inhibitor venetoclax (VEN) was used as a single agent and then was rapidly combined in VEN-based regimens associated with either anti-CD20 or with BTKi. These regimens yielded a high rate of complete remission, leading to their use as a fixed duration treatment. The decision between continuous treatment with BTKi and VEN-based combinations relies mostly on comorbidities, comedications, and patient/physician preferences. Notably, with BTKi, cardiovascular comorbidities, hypertension, and potential pharmacological interactions should be carefully evaluated. On the other hand, the risk of tumor lysis syndrome with VEN should be monitored at treatment initiation. TP53 alteration and IGHV mutational status should also be assessed, as they remain important for therapeutic decisions. Fit patients with a TP53 wild type and IGHV-mutated CLL may still benefit from fludarabine-cyclophosphamide-rituximab chemoimmunotherapy (CIT), as it may result in a very long remission duration. VEN-based treatments are well tolerated, and no additional toxicity has been observed when combined with anti-CD20 or BTKi. The 1-year fixed-duration association of VEN plus obinutuzumab was evaluated in frontline for older adult patients. Nonetheless, considering the favorable outcome, an extension of indication for fit younger patients is expected. The association of VEN and BTKi is promising, even if the follow-up is still short. It is currently being tested against CIT, BTKi continuous treatment, and VEN plus anti-CD20.