First line therapies for chronic lymphocytic leukemia (CLL) have developed beyond the historic approach of giving all patients FCR chemoimmunotherapy. In this video, recorded at the 2018 Society of Hematologic Oncology (SOHO) Annual Meeting in Houston, TX, Nitin Jain, MD, from the MD Anderson Cancer Center, Houston, TX, discusses how drugs like ibrutinib have transformed the first line therapy landscape. He also explains how improved understanding of genetic links to disease progression has allowed doctors to target patients with specific therapies, using the example of IGVH mutated patients, who respond exceptionally well to FCR. Finally, he touches on how physicians should aim to enroll older, IGVH non-mutated, or deletion 17p patients in clinical trials to improve their chances of response with novel agent therapies.