The use of immunoglobulin G (IgG) replacement therapy for primary immunodeficiency disorders has evolved over the years. Refinements in manufacturing processes and dosing regimens have improved the safety of this treatment while also improving the prospects for optimal clinical outcomes. Of particular importance has been the recognition that IgG serum trough levels ≥500 mg/dL are associated with a significant decrease in the risk of infections. Whereas some investigators have recommended titrating IgG doses to achieve uniform levels in all patients, others have suggested targeting doses to attain a so-called “biologic IgG level” individualized for each specific patient. Continuous monitoring of symptoms allows the clinician to adjust the IgG dose and/or infusion frequency according to the patient’s response. Immunoglobulin replacement therapy is a crucial and potentially life-saving treatment for patients with immunodeficiency diseases. A growing understanding of the nature of these disorders, which impair vital immunologic defenses and increase susceptibility to infections, has led to refinements in therapeutic interventions. Of particular note have been emerging insights into modified approaches to intravenous immunoglobulin G (IGIV) therapy that may enhance prospects for positive outcomes.