Scleromyxedema is a rare disease characterized by papular mucinous deposits, dermal fibroblast proliferation, and a monoclonal paraproteinemia. Its chronic course tends to be complicated by gastrointestinal, muscular, pulmonary, and neurologic disorders. We review the literature to identify the common systemic manifestations and suggest a clinical approach to this disorder. This should include: identification of the characteristic lesions, a skin biopsy, and serum protein electrophoresis. A thyroid evaluation may help differentiate this condition from others. An early neurologic, gastrointestinal, and cardiovascular evaluation should be considered.