Despite major improvements in the treatment landscape of chronic lymphocytic leukemia (CLL), infections remain the major cause of death for patients with CLL. Management of infections in patients with CLL includes antimicrobial therapy, prophylactic vaccinations, and immunoglobulin replacement. Prognostic tools to identify patients with CLL at high risk of infections are warranted. Comorbidities, history of infections, and patient preferences should be considered in addition to molecular prognostic markers when choosing treatment strategy for patients with CLL. Targeted, sequential doublet therapy may provide similar efficacy with less immunosuppression as compared to triplet targeted therapy and indefinite monotherapy.