Roughly 30-40% of diffuse large B-cell lymphomas (DLBCL) arise primarily in extranodal sites. Most frequently, they occur in the gastrointestinal tract, especially in the gastric mucosa. They also occur in the central nervous system, as testicular lymphomas, in the lungs, or in the skin. Morphologically, they show the whole spectrum of peripheral B-blasts: centroblasts, immunoblasts, or plasmoblasts. Thus, there is no actual difference in their cytomorphological presentation compared to their nodal-and frequently systemic-counterparts. However, recent data point to profound differences in primary extranodal DLBCL compared to primary nodal tumors, as well as to each other, frequently relating to their molecular characteristics and especially implying organotypic features. These characteristics may relate to a particular organotypic site of origin, or the particular clinico-pathogenetic setting in which the tumors arise. This is exemplified in the description of the DLBCL subtypes as defined by the World Health Organization classification (mediastinal or intravascular B-cell lymphoma; primary effusion lymphoma). On the other hand, primary extranodal DLBCL are frequently characterized by a particular (cyto-)genetic constitution, often related to their site of origin. Finally, some preliminary data on gene expression profiling strongly argue in favor of particular gene signatures for primary extranodal DLBCL, and hence in favor of particular organotypic transformation pathways.