The definition of Waldenström macroglobulinemia (WM), originally described in 1944, has been refined substantially over time. The current fourth edition of the World Health Organization of lymphoid neoplasms, in large part, adopted criteria proposed for WM at a consensus conference in 2002. WM is defined as lymphoplasmacytic lymphoma involving the bone marrow associated with a serum immunoglobulin (Ig) M paraprotein of any concentration. Morphologically, WM is composed of a variable mixture of lymphocytes, plasmacytoid lymphocytes, and plasma cells. Immunophenotypically, the neoplastic cells express monotypic IgM and light chain: B lymphocytes express pan-B-cell antigens and surface Ig are usually negative for CD5 and CD10; and plasma cells are typically positive for CD138, CD38, CD45, cytoplasmic Ig, and CD19 (in a substantial subset of cases). The putative cell of origin of WM is a postantigen selected memory B-cell that has undergone somatic hypermutation. The most common cytogenetic abnormality in WM is del(6q), usually in the region 6q23-24.3, present in 40% to 50% of cases. IGH gene translocations are rare and recurrent chromosomal translocations or gene aberrations have not been identified in WM. Here, we provide a historical perspective of WM, review clinical and pathologic aspects of the disease as it is currently defined, and discuss some practical issues in the differential diagnosis of WM that pathologists encounter in the signout of cases.