Determining the optimal treatment regimen for patients with chronic lymphocytic leukemia (CLL) has been a clinical challenge, especially since most patients are older than 70 years, present with significant coexisting comorbidities, and exhibit one or more common chromosomal alterations. However, outcomes in CLL are improving with the availability of non-chemotherapy options with fewer toxicities. Fixed-duration therapy has emerged as an even more attractive approach for the frontline treatment of CLL and is associated with mild toxicities, improved treatment adherence and monitoring, and reduced financial burden. Embark on a journey through this educational series to achieve a better understanding of the rationale and supporting clinical data for fixed-duration therapy, monitoring strategies, the role of MRD-guided treatment selection, and approaches to overcome relapsed/refractory CLL.