To review the different causes of secondary immunodeficiencies and provide clinicians with an updated overview of potential factors that contribute to immunodeficiency.Recent published literature obtained through PubMed database searches, including research articles, review articles, and case reports.PubMed database searches were conducted using the following keywords: immunodeficiency, antibody deficiency, immunosuppressive drugs, genetic syndrome, malignancy, HIV infection, viral infection, secondary immunodeficiency, nutrition, prematurity, aging, protein-losing enteropathy, nephropathy, trauma, space travel, high altitude, and ultraviolet light. Studies published in the last decade and relevant to the pathogenesis, epidemiology, and clinical characteristics of secondary immunodeficiencies were selected and reviewed.Researchers continue to investigate and report abnormal immune parameters in the different entities collectively known as secondary immunodeficiencies. Immunodeficiency might occur as a consequence of malnutrition, metabolic disorders, use of immunosuppressive medications, chronic infections, malignancies, severe injuries, and exposure to adverse environmental conditions. The neonate and the elderly may have decreased immune responses relative to healthy adults. Each of these conditions may present with different immune defects of variable severity. The acquired immunodeficiency syndrome results from infections by the human immunodeficiency virus, which targets CD4 T cells leading to defective immune responses. Rituximab is a monoclonal antibody that targets CD20 B cells, and its use might result in persistent hypogammaglobulinemia.Clinicians should consider secondary immunodeficiencies in the differential diagnosis of a patient with recurrent infections and abnormal immunologic evaluation. The use of biological agents for the treatment of inflammatory conditions and malignancies is an increasingly important cause of secondary immunodeficiency.