Waldenström macroglobulinemia is a B-cell malignancy with lymphoplasmacytic infiltration in the bone marrow or lymphatic tissue and a monoclonal immunoglobulin M protein (IgM) in the serum. It is incurable with current therapy, and the decision to treat patients as well as the choice of treatment can be complex. Using a risk-adapted approach, we provide recommendations on timing and choice of therapy. Patients with smoldering or asymptomatic Waldenström macroglobulinemia and preserved hematologic function should be observed without therapy. Symptomatic patients with modest hematologic compromise, IgM-related neuropathy that requires therapy, or hemolytic anemia unresponsive to corticosteroids should receive standard doses of rituximab alone without maintenance therapy. Patients who have severe constitutional symptoms, profound hematologic compromise, symptomatic bulky disease, or hyperviscosity should be treated with the DRC (dexamethasone, rituximab, cyclophosphamide) regimen. Any patient with symptoms of hyperviscosity should first be treated with plasmapheresis. For patients who experience relapse after a response to initial therapy of more than 2 years' duration, the original therapy should be repeated. For patients who had an inadequate response to initial therapy or a response of less than 2 years' duration, an alternative agent or combination should be used. Autologous stem cell transplant should be considered in all eligible patients with relapsed disease.