Over the past decade, the introduction of humanized mouse models, especially the transplantation of full-thickness human skin with autologous immune cells onto severe combined immunodeficient (SCID) mice, has transformed pre-clinical dermatology. These composite grafts vascularize and reinnervate within days, retain normal human architecture, evade graft-versus-host disease, and faithfully recapitulate complex cutaneous conditions such as psoriasis, atopic dermatitis, alopecia areata, androgenetic alopecia, vitiligo, pemphigus, and even intrinsic skin aging. Because the grafts respond to murine neuro-endocrine stress pathways yet remain immunologically human, investigators can track how psychological stress, cytokine networks, or targeted drugs shape disease onset, flare, and resolution in a living mini-patient. Unlike conventional murine models, which often capture only a single disease facet and vary by strain, humanized xenografts predict clinical efficacy, metabolism, and toxicity with far greater fidelity, enabling the discovery of pivotal mechanisms (e.g., vascular endothelial growth factor A-driven rejuvenation of aged skin [VEGF-A], voltage-gated potassium channel [Kv1.3], blockade in psoriasis, and alopecia areata) and accelerating the rational design of therapies from Janus kinase (JAK) inhibitors to neurokinin-1 receptor (NK-1R) antagonists. Although access to donor tissue and the need for pathogen-free facilities remain practical hurdles, these models now represent the gold standard for bridging bench and bedside in cutaneous research and for de-risking novel dermatologic and anti-aging interventions before they enter human trials.