<p>This review examines the regulatory roles of the IL-2 cytokine family in maintaining or disrupting skin barrier immunity, focusing on mechanisms that impair or restore barrier function and their therapeutic exploitation. A narrative review of PubMed and Google Scholar literature up to November 2025 was conducted. The IL-2 cytokine family, which includes IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, shapes cutaneous immunity through effects on keratinocyte differentiation, T-cell activation, barrier protein expression, and inflammatory signaling. Among these cytokines, IL-4 occupies a pivotal position by programming type 2 immunity and cooperating with IL-13, a non-IL-2-family cytokine, to directly suppress filaggrin, loricrin, and lipid metabolism genes, leading to increased transepidermal water loss. IL-2 functions mainly as an upstream immune modulator that regulates effector and regulatory T-cell responses and indirectly influences barrier integrity. IL-7 and IL-15 have context-dependent effects, supporting tissue-resident memory T-cell survival and repair in some models while amplifying inflammation in others. IL-9 and IL-21 also show variable roles, enhancing inflammatory signaling in atopic dermatitis and psoriasis but sometimes contributing to immune resolution or wound repair. Preclinical strategies that target these cytokines, including plant-derived agents, pathway-specific inhibitors, IL-15 modulation, and nanotechnology-based delivery systems, have improved structural proteins, lipid balance, and inflammatory biomarkers in experimental models. Nanocarriers delivering rapamycin, cyclosporine, or ceramide-enriched formulations have enhanced epidermal recovery and immune regulation. Clinical data highlight the dominance of IL-4-driven pathways. IL-4Rα blockade with dupilumab produced marked improvement in barrier integrity and disease severity across age groups, with EASI reductions of up to 92% and sustained control in patients who previously failed ciclosporin. Next generation IL-4Rα inhibitors such as rademikibart and stapokibart have also produced rapid and durable benefits. Modulation of other IL-2-family members has produced mixed outcomes. Omalizumab provided limited benefit in severe atopic dermatitis, while ultra-low-dose IL-4, IL-10, and IL-11 improved epidermal architecture in psoriasis. Overall, IL-4 serves as the principal IL-2-family effector that drives barrier dysfunction, while other members such as IL-2, IL-7, IL-9, IL-15, and IL-21 exert diverse and context-dependent regulatory functions. These pathways represent promising therapeutic targets for restoring epidermal integrity in chronic inflammatory skin disease.</p>