Abstract Chronic lymphocytic leukemia has a highly variable disease course across patients, thought to be driven by the vast inter- and intrapatient molecular heterogeneity described in several large-scale DNA-sequencing studies conducted over the past decade. Although the last 5 years have seen a dramatic shift in the therapeutic landscape for chronic lymphocytic leukemia, including the regulatory approval of several potent targeted agents (ie, idelalisib, ibrutinib, venetoclax), the vast majority of patients still inevitably experience disease recurrence or persistence. Recent genome-wide sequencing approaches have helped to identify subclonal populations within tumors that demonstrate a broad spectrum of somatic mutations, diverse levels of response to therapy, patterns of repopulation, and growth kinetics. Understanding the impact of genetic, epigenetic, and transcriptomic features on clonal growth dynamics and drug response will be an important step toward the selection and timing of therapy.