The current standard treatment for patients with chronic lymphocytic leukemia who require therapy is chemoimmunotherapy. However, the availability of an increasing number of targeted agents and combination warrants a reassessment of that approach. The high rate of durable responses with ibrutinib in relapsed refractory patients has established its role in this setting; however, because of its impressive efficacy as initial treatment, it should be considered as part of the algorithm in appropriate patients. There is virtually no role for chemotherapy in the relapsed or refractory setting, but, instead, consideration of active agents including idelalisib plus rituximab, or, particularly venetoclax. For patients with 17p-deletion, ibrutinib is the treatment of choice, with venetoclax in the setting of intolerance or relapse. Challenges include developing strategies to limit the duration of these expensive therapies, and to develop combinations with the potential to cure patients with chronic lymphocytic leukemia.