Symptomatic cryoglobulinemia

•Treatment of symptomatic cryoglobulinemia is exceedingly challenging due to the multisystemic nature of its presentation, the variability of its course, and the paucity of effective therapeutic options supported by randomized controlled clinical trials.•Patients with mild, relatively asymptomatic disease should be observed without introduction of systemic therapy.•Patients with symptomatic type I secondary cryoglobulinemia should be treated as appropriate for their underlying lymphoproliferative or plasmaproliferative disorder.•Patients with secondary type II or type III cryoglobulinemia should be treated for their underlying connective tissue, lymphoproliferative, or liver disorder or infection.•First line treatment for symptomatic, essential type II or type III cryoglobulinemia associated with hepatitis C should include interferon (IFN)-a. Depending on the severity of clinical presentation, adjuvant corticosteroids or plasmapheresis should be considered.•Life-threatening or acute organ-threatening presentations should be managed with combined modality therapy, which should include high-dose corticosteroid, plasmapheresis, or alkylator-based therapy.•Many chemotherapeutic and immunosuppressive strategies have been tried but not systematically tested; their value is therefore unknown.•Challenges for the future of treating symptomatic cryoglobulinemia include devising better therapies and more systematic evaluation of existing therapies.