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Targeted therapies have transformed the treatment landscape for patients with chronic lymphocytic leukemia (CLL). These therapies include the selective B-cell lymphoma-2 (BCL-2) inhibitor venetoclax and Bruton's tyrosine kinase (BTK) inhibitors (e.g., ibrutinib, acalabrutinib, zanubrutinib). Especially in a setting of long-term care, safety and tolerability are important considerations. Although generally well tolerated, targeted therapies for relapsed and refractory CLL are associated with potentially treatment-limiting untoward effects, often within weeks to months of initiating therapy. These include myelosuppression (e.g., neutropenia); tumor lysis syndrome, infection, and gastrointestinal effects with venetoclax; as well as cardiovascular diseases (e.g., hypertension, atrial fibrillation/flutter) and infection (e.g., pneumonia) with BTK inhibitors. Instrumental to management of these adverse effects are effective risk assessment, stratification, and modification; prophylaxis; and regimen modifications, with appropriate measures to minimize pharmacokinetic interactions.