Waldenström's macroglobulinemia (WM) is a clinical syndrome with diverse prognoses, and not all patients require therapy at diagnosis. Serum beta2 microglobulin is a major prognostic determinant, and asymptomatic patients with low beta2 microglobulin levels and preserved hemoglobin can be observed over long periods without therapy. Low-dose alkylating agents and purine analogs are commonly employed as initial therapy but rarely yield complete remissions. Patients who are refractory to or have relapse after alkylator or purine analogue therapy can be salvaged with purine analogs. Improvement in outcome demands a comprehensive approach aimed at increasing and sustaining complete remissions. Such an approach should probably employ Rituxan (IDEX Pharmaceuticals, La Jolla, CA) in conjunction with induction therapy, peripheral stem cell procurement before purine analog therapy, and high-dose therapy followed by maintenance therapy with interferon.