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The liver's inherent tolerogenic environment, combined with the immunologic immaturity and thymic activity of children, may promote this phenomenon. Achieving operational tolerance (OT) minimizes lifelong immunosuppression (IS) toxicity, improving allograft longevity and quality of life. This review synthesizes current clinical and mechanistic evidence on immune tolerance in pediatric LT, evaluating the prevalence and outcomes of IS\u2010withdrawal trials (e.g., WISP\u2010R, iWITH, LIFT, OPTIMAL, SPLIT, ALLTOL). It also examines histopathologic correlations, clinical and immunologic predictors, and underlying molecular mechanisms and cell types such as regulatory T\u2010cells, IL\u201010, TGF\u2010\u03b2, CTLA\u20104 pathways, and so forth. It addresses the challenges and limitations in translating these advances into widespread clinical practice. OT is achievable in 15%\u201360% of carefully selected pediatric LT recipients in structured IS withdrawal protocols. Tolerant children maintain normal graft function, excellent survival, and preserved immunity without increased infection risk or the cumulative toxicities of chronic IS. Predictors of OT include younger age at transplant or withdrawal, non\u2010immune disease etiology, longer post\u2010transplant duration, and absence of donor\u2010specific antibodies. Mechanistically, the liver's unique microenvironment, characterized by specific molecular pathways and cellular interactions, fosters immune regulation. Immune tolerance in pediatric LT is clinically attainable and significantly reduces the burden of lifelong IS. Progress in biomarker\u2010guided and protocolized withdrawal has improved safety, yet standardization and broader implementation remain challenges. Continued mechanistic and translational research is essential to optimize patient selection, refine monitoring strategies, and safely extend IS minimization to all pediatric LT recipients.<\/jats:p>","DOI":"10.1111\/petr.70260","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T01:39:57Z","timestamp":1767836397000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical and Experimental Immune Tolerance in Pediatric Liver Transplantation"],"prefix":"10.1111","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4773-8144","authenticated-orcid":false,"given":"Ahmed M.","family":"Elsabbagh","sequence":"first","affiliation":[{"name":"Thomas E. 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