Few prospective, randomized, placebo-controlled trials have been performed to guide clinicians in the management of neuropathies seen in the setting of monoclonal gammopathies (paraproteins). Recommendations must be made on the basis of clinical experience and information gleaned from various uncontrolled and open-label trials. In every instance, decisions concerning therapy must be based on the clinical setting in which the paraprotein occurs. Treatment of paraproteinemic neuropathies associated with multiple myeloma, amyloidosis, and Waldenström's macroglobulinemia should be directed at the treatment of the underlying disease. These neuropathies often remain recalcitrant to therapy. If the paraprotein results from cryoglobulinemia due to hepatitis C virus infection, interferon-alpha (with or without ribavirin) provides optimal subjective and objective relief from symptoms. For neuropathy associated with osteosclerotic myeloma (POEMS syndrome) and solitary bone lesions, radiation therapy is the most effective and least toxic initial therapy. In those patients with monoclonal gammopathies of undetermined significance (MGUS), consideration of the clinical syndrome may be very helpful in selecting appropriate treatment. Patients who fulfill diagnostic criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are best treated in a manner similar to that used for idiopathic CIDP (ie, with intravenous immunoglobulin, plasma exchange, and corticosteroids). Class I evidence documents plasma exchange to be effective in peripheral neuropathies associated with MGUS of the IgG and IgA, but not IgM, types. The most difficult cases to treat are those with peripheral neuropathies associated with IgM monoclonal gammopathies, with or without reactivity to myelin-associated glycoprotein (MAG). A number of published case series propose therapeutic regimens for these conditions, yet optimal treatment remains to be established. In many cases, mildly symptomatic patients should not be subjected to the morbidity associated with current treatment regimens. In those patients requiring treatment, this author initially tries plasma exchange, followed by a course of chlorambucil if the symptoms and signs are predominantly sensory. For cases with rapid progression or significant disability, a regimen of monthly pulses with prednisone and cyclophosphamide is recommended. If improvement does not ensue, a trial of a newer agent, such as rituximab, is recommended. Supportive treatment with physical therapy, orthotics, and ambulatory aids enhances patient independence at a relatively low cost.