Splenic marginal zone B cell lymphomas (SMZBCL) are rare, organotypic, lymphoid neoplasms with distinct clinicopathological features. At initial presentation, the spleen, bone marrow and peripheral blood are usually involved, while generalized lymphadenopathy is only rarely observed. Molecularly, somatic hypermutation of IgVH genes can be detected in roughly half of the cases, and deletions in 7q are present in 45% of tumors. Approximately 10%-15% of SMZBCL do occur in the setting of chronic hepatitis C. This association underlines the importance of antigenic stimulation in the proliferation of the tumor cells in HCV-associated SMBCL, if not also in their classical counterparts. More recently, gene profiling studies using cDNA microarrays revealed a homogeneous expression profile in SMZBCL, thus further confirming the notion of a distinct tumor entity. The clinical course is indolent in the majority of cases; however, some patients follow a more aggressive clinical course, usually associated with some particular molecular features in these tumors, such as unmutated IgVH genes and 7q deletions.