Therapy for chronic lymphocytic leukemia has improved dramatically over the past decade with the introduction of new targeted therapies and a paradigm shift toward targeted therapies for the majority of patients. Better understanding of prognostic factors has helped tailor therapy for individual patients, and work continues to identify optimal therapy for each patient. When therapy is required, most patients will be treated with targeted therapies, either the Bruton tyrosine kinase (BTK) inhibitors ibrutinib or acalabrutinib or the BCL-2 inhibitor venetoclax in combination with obinutuzumab. Without head-to-head comparisons showing differential efficacy among these options, considerations regarding safety, patient preference, and ability to sequence therapy currently influence treatment decisions. Also, clinical trials investigating combinations of these therapies have the potential to further change the standard of care. In this review, we cover the currently available options for the frontline treatment of chronic lymphocytic leukemia (CLL) and discuss safety considerations and toxicity management with each agent as well as novel combination strategies currently under investigation.