Since the initial identification of patients with monoclonal elevation of gamma globulin and associated clinical symptoms in 1944 by Jan Waldenström, several new insights have been gained using a range of approaches. For example, IgM monoclonal gammopathy of undetermined significance and smoldering Waldenström's macroglobulinemia are defined clinical precursor states to symptomatic Waldenström's macroglobulinemia. Epidemiologic studies have established the prevalence of these conditions and the estimated risk of progression to symptomatic disease. Recent molecular studies have identified mutations in the MYD88 and CXCR4 genes as early events in the pathogenesis of IgM MGUS and Waldenström's macroglobulinemia. In this review we summarize the epidemiologic and molecular features of Waldenström precursor states, the risk stratification and clinical evaluation of these conditions and possible management options. With the advent of more effective and safer treatments for Waldenström's macroglobulinemia, we highlight the possibility of clinical treatment trials targeting patients with smoldering Waldenström's macroglobulinemia.