Large B-cell lymphomas (LBCLs) represent a frequent but clinically and morphologically heterogeneous group of tumors. Technological advances over the last 2 decades prompted the development of new classification schemas to sharpen diagnoses, dissect molecular heterogeneity, and identify rational treatment targets. Despite increased molecular understanding of these lymphomas, the clinical perspectives of patients largely remain unchanged. Recently finished comprehensive genomic studies discovered genetically defined LBCL subtypes that predict outcome, provide insight into lymphomagenesis, and suggest rational therapies with the hope of generating patient-tailored treatments with increased perspective for patients in greatest need. Here, we summarize notable examples of how high-throughput technologies aided in better molecular understanding of LBCLs and provided examples of rationally designed targeted treatments.