Retinal lymphoma, the most common form of intraocular lymphoma, is a high-grade malignancy, usually of B-cell type, and is associated with a poor prognosis because of frequent central nervous system (CNS) involvement. The neoplastic B-cells of retinal lymphoma have a characteristic morphology and immunophenotype, express certain chemokines and chemokine receptors, and produce interleukins (IL), e.g. IL-10. Together with the cytological features of these tumors, the immunophenotype, presence of immunoglobulin rearrangements, and biochemical profile aid the diagnosis of retinal lymphomas. Immunophenotyping and somatic mutation analysis suggest derivation of most retinal lymphomas from an early post-germinal centre B-cell. Chromosomal translocation data would suggest, however, that a subgroup of these neoplasms may arise from germinal centre B-cells, and these could be associated with a better prognosis. Further investigations, such as gene expression profiling, are required to identify oncogenic pathways potentially involved in retinal lymphoma development, and to identify new prognostic/therapeutic markers for this tumor.