Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma in Western countries and represents a heterogeneous group of diseases. Historically, the disease has been stratified based solely on clinical prognostic factors, such as those that make up the International Prognostic Index (IPI). In the past decade, many advances have been made in understanding the biology of DLBCL, including clinical aspects, gene expression profiling, and microRNA. These evaluations have revealed several distinct subtypes with differing responses to therapy and different long-term outcomes, but the standard initial therapy for DLBCL continues to use regimens like R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regardless of the disease subtype. Despite improvements in the diagnosis and treatment of this condition, nearly one third of patients die of their disease. This article reviews the history of DLBCL, prognostic factors, therapy, and possible future directions.