The article provides a comprehensive overview of the molecular mechanisms underlying nucleotide excision repair (NER), a crucial DNA damage removal pathway that addresses a wide range of lesions, including those induced by environmental factors such as UV radiation. The NER process is divided into two main pathways: global genome NER (GG-NER) and transcription-coupled NER (TC-NER). GG-NER involves the removal of lesions across the entire genome, while TC-NER focuses on lesions in transcribed regions. Key components of the NER machinery include XPC-hHR23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF. XPC-hHR23B is the first factor to detect and bind to DNA lesions, recruiting other repair factors. TFIIH, a transcription factor complex, mediates strand separation around the lesion. XPA verifies the damage and stabilizes the open complex, while RPA stabilizes the undamaged strand and positions the nuclease enzymes. XPG and ERCC1-XPF make the 3′ and 5′ incisions, respectively, to remove the damaged segment. The article also discusses the role of transcription in NER, highlighting the importance of TFIIH and XPG in coupling repair to transcription. Additionally, it explores the clinical implications of NER defects, such as xeroderma pigmentosum (XP) and Cockayne syndrome (CS), and the complex interplay between these syndromes.The article provides a comprehensive overview of the molecular mechanisms underlying nucleotide excision repair (NER), a crucial DNA damage removal pathway that addresses a wide range of lesions, including those induced by environmental factors such as UV radiation. The NER process is divided into two main pathways: global genome NER (GG-NER) and transcription-coupled NER (TC-NER). GG-NER involves the removal of lesions across the entire genome, while TC-NER focuses on lesions in transcribed regions. Key components of the NER machinery include XPC-hHR23B, TFIIH, XPA, RPA, XPG, and ERCC1-XPF. XPC-hHR23B is the first factor to detect and bind to DNA lesions, recruiting other repair factors. TFIIH, a transcription factor complex, mediates strand separation around the lesion. XPA verifies the damage and stabilizes the open complex, while RPA stabilizes the undamaged strand and positions the nuclease enzymes. XPG and ERCC1-XPF make the 3′ and 5′ incisions, respectively, to remove the damaged segment. The article also discusses the role of transcription in NER, highlighting the importance of TFIIH and XPG in coupling repair to transcription. Additionally, it explores the clinical implications of NER defects, such as xeroderma pigmentosum (XP) and Cockayne syndrome (CS), and the complex interplay between these syndromes.