This episode features leading experts Paolo Ghia, MD, Vita-Salute San Raffaele University, Milan, Italy, and Arnon Kater, MD, PhD, University of Amsterdam, Amsterdam, Netherlands, who provide key insights into the management of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), guided by the latest ESMO clinical practice recommendations. They explore treatment strategies at first relapse and for double-refractory patients, including fixed-duration combinations and the emerging role of the non-covalent BTK inhibitor, pirtobrutinib. Additionally, the experts share their perspectives on the role of allogeneic stem cell transplantation and CAR T-cell therapy, and offer a glimpse into promising therapies on the horizon, such as BTK degraders and bispecific antibodies.