Approximately 10% of patients with peripheral neuropathy of otherwise unknown etiology have an associated monoclonal gammopathy. Both the neuropathies and the monoclonal gammopathies in these patients are heterogeneous, but several distinct clinical syndromes that may respond to specific therapies can be recognized. It is important to recognize these syndromes because monoclonal gammopathies also occur in 1% of the normal adult population, and in some cases, monoclonal gammopathies are coincidental and unrelated to the neuropathy. In patients with IgM monoclonal gammopathies, IgM M proteins frequently have autoantibody activity and are implicated in the pathogenesis of the neuropathy. IgM M proteins that bind to myelin-associated glycoprotein (MAG) have been shown to cause demyelinating peripheral neuropathy; anti-GM1 antibody activity is associated with predominantly motor neuropathy, and anti-sulfatide or chondroitin sulfate antibodies are associated with sensory neuropathy. The IgM monoclonal gammopathies may be malignant or nonmalignant, and polyclonal antibodies with the same specificities are associated with similar clinical presentations in the absence of monoclonal gammopathy. IgG or IgA monoclonal gammopathies are associated with neuropathy in patients with osteosclerotic myeloma or the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy myeloma, and skin changes). Amyloidosis or cryoglobulinemic neuropathies can occur with either IgM or IgG and IgA monoclonal gammopathies. Therapeutic intervention depends on the specific clinical syndrome but is generally directed at removing the autoantibodies, reducing the number of monoclonal B cells, and interfering with the effector mechanisms.