Since the first description of mucosa-associated lymphoid tissue (MALT) lymphoma in 1983 rapid advances have been made in the understanding of the pathogenesis and underlying molecular events associated with the development of this tumor. Lymphoma arises at extranodal sites in which a pre-existing inflammatory response has provoked the acquisition of organized lymphoid tissue. Specific molecular events have been associated with the development of MALT lymphoma including t(11;18) and alterations in Bcl-10 protein expression, and these appear to be interlinked. In gastric MALT lymphoma Helicobacter pylori is the most common stimulus for the acquisition of lymphoid tissue. Eradication of this organism has been shown to result in regression of the tumor in many cases, but there are a few that will not respond to this approach. Predicting those cases unlikely to respond to H pylori eradication alone has been investigated in a number of ways. An underlying t(11;18) within the tumor cells appears to predict for a lack of response. Clinical measurement of the depth of infiltration of the wall by gastric MALT lymphoma as measured by endoscopic ultrasound has been less clear. More superficial tumors are more likely to respond, but regression has been reported even in cases with local lymph node involvement. For superficial lymphomas at other sites alternatives to radiotherapy, chemotherapy, or surgery have been sought. Local injections of interferon (IF) alpha have been successful in treating conjunctival lymphoma, and this approach may be of use for other superficial lesions.