Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by defective UV radiation-induced DNA repair, leading to photosensitivity, early skin cancer, and neurodegeneration. It affects approximately 1 in a million people in the US and 45 in a million in Japan. XP is associated with multiple complementation groups, each with distinct genetic and clinical features. The disease is caused by mutations in genes involved in the nucleotide excision repair (NER) pathway, which is crucial for repairing UV-induced DNA damage. Patients with XP are at high risk for skin cancers, including squamous cell carcinoma, basal cell carcinoma, and melanoma, as well as neurodegenerative conditions and ocular abnormalities. XP patients also experience premature skin aging, with features like atrophy, dryness, and abnormal pigmentation. The most common complementation groups are XPC, XPE, and XPV, with XPC being the most common in the US and Europe, and XPA in Japan. XPV is a variant with normal DNA repair but a mutation in DNA polymerase η. Patients with XP have a significantly increased risk of developing skin cancer and neurodegenerative diseases, with a median age of death around 29 years for those with neurodegeneration. Prevention through UV protection, vitamin D supplementation, and early treatment of skin lesions can improve outcomes. There is currently no cure for XP, but research into gene therapy and antioxidants offers potential future treatments. XP has been a valuable model for understanding DNA repair mechanisms and UV-induced cancer.Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder characterized by defective UV radiation-induced DNA repair, leading to photosensitivity, early skin cancer, and neurodegeneration. It affects approximately 1 in a million people in the US and 45 in a million in Japan. XP is associated with multiple complementation groups, each with distinct genetic and clinical features. The disease is caused by mutations in genes involved in the nucleotide excision repair (NER) pathway, which is crucial for repairing UV-induced DNA damage. Patients with XP are at high risk for skin cancers, including squamous cell carcinoma, basal cell carcinoma, and melanoma, as well as neurodegenerative conditions and ocular abnormalities. XP patients also experience premature skin aging, with features like atrophy, dryness, and abnormal pigmentation. The most common complementation groups are XPC, XPE, and XPV, with XPC being the most common in the US and Europe, and XPA in Japan. XPV is a variant with normal DNA repair but a mutation in DNA polymerase η. Patients with XP have a significantly increased risk of developing skin cancer and neurodegenerative diseases, with a median age of death around 29 years for those with neurodegeneration. Prevention through UV protection, vitamin D supplementation, and early treatment of skin lesions can improve outcomes. There is currently no cure for XP, but research into gene therapy and antioxidants offers potential future treatments. XP has been a valuable model for understanding DNA repair mechanisms and UV-induced cancer.