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Waldenström Macroglobulinemia (WM) is an incurable hematologic malignancy characterized by lymphoplasmacytic infiltration of the bone marrow and the presence of monoclonal immunoglobulin (IgM). Although a portion of WM patients may experience a relatively indolent course, patients may experience IgM-related morbidity and/or disease-related mortality. This underscores the need for novel approaches to improve response and survival rates. Significant progress had been made in our understanding of the genomics and biology of WM. The discovery of the highly recurrent somatic mutations in the MYD88 gene detected in 90–95% and the CXCR4 gene detected in 30–40% of WM patients has provided an opportunity to develop novel targeted approaches. Mutational status has important implications in predicting response to therapies such as BTK inhibitors. Treatment of WM should be guided by many factors including performance status, comorbidities, goals of therapy, and toxicities. In this review, we describe how current genomics may be utilized to optimize WM treatment selection. As the therapeutic landscape of WM continues to expand with more targeted approaches, the genomics in WM will likely play a greater role in individualizing treatment. [ABSTRACT FROM AUTHOR]