The last decades have seen great progress in the treatment of cold agglutinin 
disease (CAD). Comparative trials are lacking, and recommendations must be based 
mainly on nonrandomized trials and will be influenced by personal experience. 
Herein, current treatment options are reviewed and linked to 3 cases, each 
addressing specific aspects of therapy. Two major steps in CAD pathogenesis are 
identified, clonal B-cell lymphoproliferation and complement-mediated hemolysis, 
each of which constitutes a target of therapy. Although drug treatment is not 
always indicated, patients with symptomatic anemia or other bothersome symptoms 
should be treated. The importance of avoiding ineffective therapies is 
underscored. Corticosteroids should not be used to treat CAD. Studies on safety 
and efficacy of relevant drugs and combinations are briefly described. The 
author recommends that B cell-directed approaches remain the first choice in 
most patients requiring treatment. The 4-cycle bendamustine plus rituximab 
combination is highly efficacious and sufficiently safe and induces durable 
responses in most patients, but the time to response can be many months. 
Rituximab monotherapy should be preferred in frail patients. The complement C1s 
inhibitor sutimlimab is an emerging option in the second line and may also find 
its place in the first line in specific situations.