Chronic lymphocytic leukemia (CLL) is a common B-cell malignancy with a remarkably heterogeneous course, ranging from indolent disease with no need for immediate therapy to rapidly progressive disease associated with therapeutic resistance. The recent US Food and Drug Administration approvals of novel targeted therapies such as inhibitors of B-cell receptor signaling and B-cell lymphoma 2 have opened up new opportunities in the clinical management of patients with CLL and heralded a new era in the clinical treatment of this disease. In parallel, the implementation of novel sequencing technologies has provided new insights into CLL complexity, identifying a growing list of putative drivers that underlie inter- and intratumor heterogeneities in CLL affecting disease progression and resistance. The identification of these novel genomic features that can indicate future drug resistance or guide therapeutic management is now becoming a major goal in CLL so that patients can best benefit from the increasingly diverse available therapies, as discussed herein.