Diffuse large B-cell lymphoma (DLBCL) is a biologically heterogeneous mature B-cell neoplasm whose classification, prognosis, and therapy have been reshaped by advances in genomic, transcriptomic, epigenomic, single-cell, and spatial profiling technologies. This review focuses on how these approaches have refined the molecular landscape of DLBCL, including recurrent chromosomal translocations, tumor-suppressor alterations, oncogenic signaling pathways, and tumor-microenvironment programs. Cell-of-origin (COO) frameworks remain clinically useful. However, contemporary models extend beyond conventional germinal center categories by incorporating probabilistic genetic subtypes, expression-defined high-risk states, and spatially resolved lymphoma-cell and immune-cell ecosystems. These high-resolution methods clarify intratumoral heterogeneity, identify biologically distinct subgroups, and inform prognosis and therapeutic selection. The review also summarizes how tumor-intrinsic biology and the tumor-microenvironment (TME) shape responses to frontline therapy, targeted agents, antibody-drug conjugates, bispecific antibodies, and CD19-directed CAR T-cell therapy. Particular emphasis is placed on product-specific evidence in relapsed/refractory disease, rational sequencing of immunotherapies, and emerging biomarkers such as circulating tumor DNA-based measurable residual disease (ctDNA-MRD). Together, these developments support a shift from COO-centric classification toward dynamic, biology-driven models that incorporate tumor-intrinsic and microenvironmental determinants to guide personalized therapy in DLBCL.