In this Deep Dive Session, Dr. Semira Irusen and Dr. Mark Murakami delve into the complexities of high-grade B-cell lymphomas, with a particular focus on double-hit and triple-hit lymphomas. Dr. Irusen provides a comprehensive overview of the diagnostic challenges, treatment strategies, and prognosis of these aggressive lymphomas, highlighting the need for individualized treatment plans, especially in patients with concurrent conditions like HIV. Dr Murakami then discusses the molecular biology of these lymphomas in depth, emphasizing the role of MYC and BCL2/3 gene rearrangements in their pathogenesis.