<p>The treatment of chronic lymphocytic leukemia (CLL) has changed significantly since the introduction of targeted therapies, and Bruton’s tyrosine kinase (BTK) and BCL2 inhibitors have largely replaced chemoimmunotherapy as the standard first-line therapy. Compared to chemoimmunotherapy, these targeted therapies have demonstrated superior progression-free survival (PFS) and, in some cases, overall survival (OS), particularly in patients with high-risk CLL (unmutated<i> IGHV</i>, <i>TP53</i> mutations, and/or 17p deletion). In Germany, time-limited therapies with venetoclax–obinutuzumab or venetoclax–ibrutinib and continuous, indefinite therapies with BTK inhibitors such as acalabrutinib, ibrutinib, or zanubrutinib are approved in the first-line setting. First-line treatment should only be initiated in patients with advanced and/or symptomatic disease. Key stratification factors for the choice of treatment are genetic markers, patient-specific preferences, specific comorbidities, and the expected side effect profile of the different therapies. Although no direct comparisons between time-limited venetoclax-based treatment approaches and continuous BTK inhibitor therapy exist, studies show that both approaches achieve comparable long-term results, with certain advantages in different patient groups. For patients with high-risk genetics, continuous BTK inhibitor therapy is primarily recommended, while for patients with mutated<i> IGHV</i>, venetoclax-based time-limited combinations are preferred. In summary, both time-limited venetoclax combinations and continuous BTK inhibitor therapies yield excellent long-term outcomes in the majority of patients; the choice between the two treatment paradigms should be personalized, taking into account genetic and clinical factors as well as patient-specific preferences.</p>