The introduction of human immunoglobulin (Ig) therapies 40 years ago reduced the risk of often life-threatening infections for individuals with one of several immune-related conditions known as primary immunodeficiencies. Since then, the use of Ig has expanded to numerous other conditions. However, even though less than 1% of covered lives under Medicare or commercial insurers require Ig, it is in the top 5 drug categories in terms of annual spending. The cost of Ig is directly related to the type of delivery method used and the site of care. Numerous studies attest to the efficacy and cost savings of shifting Ig to the home setting, as well as shifting patients from intravenous Ig (IVIG) to subcutaneous Ig (SCIG). In addition, surveys find that patients with primary immunodeficiencies prefer home delivery, with patient evaluations also finding a preference for SCIG. Payers have numerous options to ensure Ig is used appropriately for the right patient in the right setting. These include formulary management, site-of-care programs, education for providers and patients on the possibility of switching from IVIG to SCIG, preauthorization policies that restrict the use of Ig to certain specialties for specific indications, implementation of evidence-based coverage criteria, and shifting coverage from the medical to the pharmacy benefit.