POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome is a rare multisystemic paraneoplastic syndrome driven by an underlying plasma cell dyscrasia. More than 95% of patients will have monoclonal lambda sclerotic plasmacytoma(s) or bone marrow infiltration. Recognition of the complex of a combination of peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasmaproliferative disorder, skin changes, sclerotic bone lesions, Castleman disease, thrombocytosis, papilledema, peripheral edema, pleural effusions, ascites, fingernail clubbing, and white nails is the first step in effectively managing the disease. Once a patient has been completely evaluated, each component of the disease should be addressed, while finalizing a treatment plan for the underlying plasma cell proliferative disorder. In patients with a dominant sclerotic plasmacytoma, first-line therapy should include radiation to the lesion. Retrospective analysis and personal experience would dictate that systemic therapy be considered for patients with diffuse sclerotic lesions or absence of any bone lesion and for patients who have not demonstrated stabilization of their disease 3 to 6 months after completing radiation therapy. Treatments with demonstrated benefit include corticosteroids, low-dose alkylator therapy, and high-dose chemotherapy with peripheral blood stem cell transplant. Until the pathogenesis is fully understood, these are the mainstays of treatment for patients with POEMS syndrome.