Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, representing ~25% of new diagnoses, being the most prevalent lymphoid malignancy in adults. While standard R-CHOP immunochemotherapy induces complete remission in over 60% of cases, patients with relapsed or refractory disease have a poor 5-year survival rate of only 20%, highlighting a major unmet clinical need. DLBCL is marked by substantial heterogeneity in morphology, genetics, and biological behavior, emphasizing the need for improved molecular tools to identify high-risk patients and guide therapy. However, current approaches do not allow for upfront prediction of treatment response or timely adaptation during therapy. Moreover, repeated tissue biopsies are invasive, often impractical, and burdensome for patients. Liquid biopsies, particularly cell-free RNA (cfRNA) profiling, offer a minimally invasive alternative. cfRNA reflects real-time transcriptional activity, capturing both intra- and intertumoral heterogeneity while allowing detection of gene fusions, splice variants, and gene expression shifts— not only providing insight into tumor biology, immune modulation, and resistance mechanisms, but also helping to identify actionable targets. Given DLBCL’s high cellular turnover, cfRNA is abundantly present in plasma. Using just 200 µl of blood enables early prediction of therapy resistance, monitoring of minimal residual disease (MRD), and timely relapse detection before clinical symptoms arise. This approach supports precision oncology by enabling personalized, dynamic, and more effective patient management while reducing the need for invasive biopsies.