The term marginal-zone lymphoma (MZL) encompasses three closely related lymphoma subtypes, namely the "low-grade B-cell lymphoma of MALT type" currently named MALT lymphoma, the "nodal marginal-zone B-cell lymphoma" and a provisional entity in the REAL classification named "primary splenic MZL with or without villous lymphocytes". These entities display different characteristics, with evident clinical and biological variations according to the organ where the lymphoma arises. Marginal-zone B-cells are functionally heterogeneous and may differ with respect to the pattern of somatic hypermutation in their Ig variable genes. Sequence and mutation analysis of the rearranged Ig heavy chain variable genes and that somatic mutations pattern indicate that MZL may arise from different subsets of marginal-zone B-cells. Pathogenesis of these groups of lymphomas is correlated to chronic infections, like Helicobacter pylori, hepatitis C virus, Campylobacter jejuni, Chlamydia psittaci and Borrelia burgdorferi. Several therapeutic strategies against these malignancies exist. Surgical resection, radiotherapy and alkylating agent-based chemotherapy constitute standard approaches, while antimicrobial therapies, anti-CD20 therapy and new forms of immunotherapy constitute interesting experimental approaches. However, prospective trials on these malignancies are rare and universally accepted therapeutic guidelines do not exist. MZLs constitute an exciting investigational setting both from molecular and clinical points of view.