Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 40% of all B-cell non-Hodgkin lymphomas of the Western world. According to the "WHO classification of tumours of the haematopoietic and lymphoid tissues", the term DLBCL is likely to include more than one disease entity, as suggested by the marked variability of the clinical presentation and response to treatment of this disease. Such heterogeneity may reflect the occurrence of distinct molecular subtypes of DLBCL as well as differences in the host's immune function. In immunocompetent hosts, approximately 50% DLBCL carry one of two primary molecular lesions defining two distinct genotypic subgroups, characterized by activation of either the BCL-6 or the BCL-2 proto-oncogene. Conversely, the remaining DLBCL of immunocompetent hosts display one of several molecular lesions, each associated with a small subset of cases and including activation of the proto-oncogenes REL, MUC-1, BCL-8 and c-MYC. The molecular pathogenesis of immunodeficiency-associated DLBCL differs substantially from that of DLBCL in immunocompetent hosts. In fact, EBV infection is present in a large fraction of immunodeficiency-associated DLBCL, whereas it is consistently negative in DLBCL of immunocompetent hosts, probably reflecting the critical role of disruption of the immune system in this disease. Finally, the application of DNA microarray technology to DLBCL has led to the distinction of two disease variants: a germinal center like DLBCL and an activated peripheral B-cell like DLBCL. Overall the molecular features of DLBCL may identify prognostic categories of the disease and may represent a powerful tool for therapeutic stratification.