B cell receptor (BCR) sequencing has been the driving force behind many recent advances in chronic lymphocytic leukemia (CLL) research. Here, we discuss the general principles, revelations and applications of reading the BCR immunome in the context of CLL. Firstly, IGHV mutational status, obtained through measuring the mutational imprint on the IGHV gene of the CLL clonotype, is the cornerstone of CLL risk stratification. Furthermore, the discovery of ‘BCR-stereotyped’ groups of unrelated patients that not only share a highly similar BCR on their leukemic clone, but also certain clinical characteristics, has provided insights key for understanding disease ontogeny. Additionally, whereas the BCR repertoire of most CLL patients is characterized by a single dominant rearrangement, next generation sequencing (NGS) has demonstrated a rich subclonal landscape in a larger than previously expected proportion of CLL patients. We review the mechanisms behind these ‘multiple dominant’ cases, including V(D)J-recombination errors, failure of allelic exclusion, intraclonal diversification and ‘true’ bi- or oligoclonality, and their implications, in detail. Finally, BCR repertoire sequencing can be used for sensitive quantification of minimal residual disease (MRD) to potentially unprecedented depth. To surmount pitfalls inherent to this approach and develop internationally harmonized protocols, the EuroClonality-NGS Working Group has been established.Copyright © 2020. Published by Elsevier Inc.