Diffuse large B-cell lymphoma (DLBCL) is an aggressive subtype of non-Hodgkin's lymphoma that arises from the germinal center. It represents a heterogeneous disease characterized by different pathological, clinical, and molecular entities. Gene expression profiling based on the alleged cell of origin differentiates transcriptional subtypes such as germinal center and activated B cell-like. DLBCL accounts for around 40% of all non-Hodgkin's lymphomas worldwide. Its incidence generally increases with age. The international prognostic index remains the most important tool for disease stratification.The diagnosis of DLBCL is best made through an excisional biopsy of a suspicious lymph node. Nowadays, advanced techniques are employed to accurately diagnose and determine the clinical outcomes of patients. Immunohistochemistry, next-generation sequencing, and array-based comparative hybridization facilitate the global identification of diverse and numerous genetic alterations. However, further validation should be necessary to apply advanced techniques in clinical practice. In this review, we summarize the current literature and discuss the pathophysiology, epidemiology, and diagnostic advancements of DLBCL.