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Inhibitors of PDE4 have emerged as safe and effective anti\u2010inflammatory therapies across multiple dermatologic diseases, and growing evidence suggests that PDE4 inhibition exerts broader effects on skin physiology. This review synthesizes mechanistic, preclinical, and clinical evidence describing the multifaceted roles of PDE4 inhibition in the skin. A comprehensive literature review was conducted using PubMed\/MEDLINE, Embase, and\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link>\n                    through 2025. Search terms included \u201cPDE4,\u201d \u201cphosphodiesterase 4,\u201d and both approved and investigational therapies, including \u201capremilast,\u201d \u201ccrisaborole,\u201d \u201croflumilast,\u201d and \u201corismilast.\u201d Relevant preclinical studies, clinical trials, and mechanistic investigations were included. PDE4 inhibition prevents cAMP degradation and activates protein kinase A (PKA) signaling, leading to broad biologic effects in the skin. Beyond well\u2010established anti\u2010inflammatory actions, PDE4 inhibitors appear to influence melanocyte signaling and pigmentation, enhance epidermal barrier protein expression, modulate sensory neuron activity, and promote wound healing by reducing fibrosis. These effects have been demonstrated mechanistically and across multiple dermatologic conditions and may help explain clinical observations. Heterogeneity in study design, limited long\u2010term data, and variability in PDE4 isoform selectivity across studies may limit generalizability. Further mechanistic and comparative clinical studies are needed to better define therapeutic impact. PDE4 inhibitors represent a unique therapeutic class with pleiotropic effects across multiple disease states, including regulation of pigmentation, barrier integrity, neural signaling, and tissue repair. Their ability to integrate immunologic and non\u2010immunologic pathways highlights their role in maintaining cutaneous homeostasis and expanding therapeutic potential in dermatology.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/ijd70456-gra-0001-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  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