Matthew S. Davids, MD, MMSc; Alvaro Alencar, MD; Marc S. Hoffmann, MD; Brad S. Kahl, MD, and Nicole Lamanna, MD,engage in a comprehensive discussion of frontline CLL treatment strategies, examining factors influencing the choice between fixed-duration venetoclax-based therapy and continuous BTK inhibitors, analyzing long-term SEQUOIA trial data, evaluating real-world outcomes and adverse events with covalent BTK inhibitors, and assessing emerging combination approaches including zanubrutinib plus venetoclax.