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Despite its significant cure rate, diffuse large B‑cell lymphoma (DLBCL) remains a tumor entity of unmet medical need. The 2019 meeting of the American Society of Hematology (ASH) in Orlando, Florida, presented numerous directions, whereby clinicians may expect practice-changing innovations soon or in the near future. In this ASH highlight feature on “aggressive B‑cell lymphoma”, a selection of prominent findings will be summarized. Targeted therapeutics try to meet the needs of patients subgroups that would benefit, and novel immune oncology agents now represent established treatment principles for relapsed/refractory (R/R) DLBCL. Moreover, intense research efforts have been undertaken to identify biomarkers of response. Imaging-based and molecular diagnostic tools are becoming increasingly instrumental in appraising individual risk prior to the first treatment encounter and in the early phase of induction therapy. Genomic analyses of circulating tumor DNA conducted in the peripheral blood has gained attention in terms of assigning patients to dedicated tumor subtypes, monitoring their molecular tumor burden in the course of the disease, and steering personalized treatment extensions in the near future.