The proper development and function of T cells is imperative in the creation of adequate cell-mediated and humoral immunity. Healthy term newborns have baseline immune immaturity, increasing their risk of infections, but significant immunologic consequences can occur, because of abnormal T-cell maturation. Combined immunodeficiencies can result, because B cells and natural killer cells rely on successful interactions with T cells to ensure their proper performance and survival. Severe combined immunodeficiency (SCID) is the most noteworthy of these conditions, leading to considerable early morbidity and often death by the age of 1 year if left untreated. Newborn screening for SCID is effective and allows for early implementation of lifesaving supportive measures, including protective isolation, initiation of prophylactic antimicrobials, caution with blood product transfusions, and avoidance of live vaccinations. Once a definitive diagnosis of SCID has been established, treatment frequently involves bone marrow or stem cell transplantation; however, enzyme replacement and gene therapy are also becoming options in those with SCID due to adenosine deaminase deficiency and other forms of SCID. Neonatal clinicians should understand the screening and diagnostic approach to SCID along with the initial management approaches for these extremely high-risk patients.