There are three different marginal zone lymphoma (MZLs) entities: the extranodal MZL of mucosa- associated lymphoid tissue, the splenic MZL, and the nodal MZL. The 3 MZLs share common lesions (trisomies of chromosomes 3 and 18, deletions at 6q23), and alterations of the nuclear factor κB pathway are frequent events in all of them, but they also differ in the presence of recurrent translocations, mutations affecting the NOTCH pathway, and the transcription factor Kruppel-like factor 2 (KLF2) or the receptor-type protein tyrosine phosphatase delta (PTPRD). This review outlines the most recent and main advances in our understanding of the genetics and biology of MZLs and summarizes the clinical activity of the novel therapeutic approaches targeting the main druggable pathways. The current principles of the standard management of MZL at different anatomic sites are also discussed.