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The last 10 years have seen a number of changes that have made a tremendous impact in the management of patients with chronic lymphocytic leukemia (CLL): A better understanding of the biology of the disease, characterization of sub-populations at risk, and the development of oral therapies. Currently, Bruton’s tyrosine kinase inhibitors (BTKis) and the B-cell lymphoma 2 inhibitor (BCL2i) venetoclax are standard first-line and relapse treatments, as monotherapy or in combination. However, treatment sequences (continuous or fixed-duration) and optimal combinations have yet to be defined. In this review, we will focus on the management of relapsed patients. We will discuss the important elements to consider when choosing treatment and, more generally, in the strategy for treatment lines. Recent advances in this disease represent significant progress and raise new questions about how available drugs should be used and how we can continue to improve CLL treatment.