Recent studies on normal and malignant B-cells have provided evidence that the germinal center (GC) of lymphoid follicles exerts a role in B-cell physiology and malignancy. GC-derived lymphomas include both B-cell and T-cell lymphomas. Remarkably, tumor cells of GC-derived lymphomas proliferate in close association with cellular environment that retains key features of normal GC cellular microenvironment. Neoplastic follicles in follicular lymphoma contain, in addition to follicular dendritic cells (FDC) other non-neoplastic cells including macrophages and GC T-cells. In addition to aggregates of FDCs, the background infiltrate of nodular lymphocyte predominant Hodgkin lymphoma includes small B-cells, T-cells, and histiocytes. Typically, most of the lymphocyte predominant (LP) cells are ringed by CD3+/CD4+ T-cells expressing CD57, PD1, BCL6, and MUM1/IRF4. By contrast, Reed-Sternberg cells of classic Hodgkin lymphoma (cHL) are surrounded by CD3+/CD4+ T-cells expressing CD40L. Unlike cHL and other peripheral T-cell lymphomas, the AITL microenvironment characteristically contain a prominent proliferation of high endothelial venules and FDC. Thus, these findings shed new light on the characterization of GC-derived lymphomas and may help in the differential diagnosis and acknowledge several novel pathogenetic mechanisms on these lymphomas. Am. J. Hematol., 2009. (c) 2009 Wiley-Liss, Inc.