Antigen-driven selection has been implicated in the pathogenesis of monoclonal gammopathies. Patients with Gaucher's disease have an increased risk of monoclonal gammopathies and symptomatic myeloma. Clonal immunoglobulin in patients with Gaucher's disease and in mouse models of Gaucher's disease-associated gammopathy are reactive against lyso-glucosylceramide (LGL1), which is markedly elevated in these patients and mice. A recent report indicates that clonal immunoglobulins in 33% of sporadic human monoclonal gammopathies may also be specific for the lysolipids LGL1 and lysophosphatidylcholine. Substrate reduction ameliorates Gaucher's disease-associated gammopathy in mice. This principle (that antigen removal can induce tumor regression) has been proven in other hematologic malignancies, where H. Pylori eradication causes lymphoma regression is a significant group of patients. Thus, as longterm immune activation by lysolipids may underlie both Gaucher's disease-associated gammopathies and some sporadic monoclonal gammopathies, this may represent a focus for treatment.