Asthma and allergy are two prevalent immune-mediated disorders caused by an excess of T-helper (TH) cell activity, i.e., an example of TH2 predominance with elevated IgE, eosinophilia and chronic airway inflammation. Of special importance, immune checkpoint receptor cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) were observed to regulate T-cell regulation and TH1/TH2 immunobalance of immunity through competitive blocking of CD28 interaction with B7 ligands on antigen-presenting cells to inhibit T-cell activation. Functional polymorphisms like +49 A/G (rs231775), −318 C/T (rs5742909) and CT60 A/G (rs3087243) of the CTLA4 gene have been associated with regulated CTLA-4 expression and function with implications for asthma and allergy susceptibility. This review collates contemporary understanding of CTLA-4 structure biology, its TH1/TH2 polarizing immunomodulatory roles, and genetic variants' effects on allergic phenotypes across diverse populations. Some CTLA-4 polymorphisms disrupt immune regulation, promoting TH2 dominance, IgE synthesis, airway hyperresponsiveness, and atopic disease progression by undermining regulatory mechanisms. Ethnic variation in CTLA-4 variants may serve as biomarkers for disease susceptibility and treatment response, potentially even to corticosteroids and biologics. Rising preclinical data also show the potential of CTLA-4–targeted therapies to regulate allergic inflammation. Current evidence is hampered by small cohorts, limited ethnic diversity, and replication constraint in genome-wide studies. We conclude by outlining areas of unknowns and proposing future research directions to determine genotype–phenotype relationships and integrate CTLA-4 findings into individualized interventions for allergy and asthma. Understanding the immunogenetic landscape of CTLA-4 will enhance precision immunology and inform new treatments against these global disease burdens.