Nucleotide excision repair (NER) is one of the major cellular pathways that removes bulky DNA adducts and helix-distorting lesions. The biological consequences of defective NER in humans include UV-light-induced skin carcinogenesis and extensive neurodegeneration. Understanding the mechanism of the NER process is of great importance as the number of individuals diagnosed with skin cancer has increased considerably in recent years, particularly in the United States. Rapid progress made in the DNA repair field since the early 1980s has revealed the complexity of NER, which operates differently in different genomic regions. The genomic heterogeneity of repair seems to be governed by the functional compartmentalization of chromatin into transcriptionally active and inactive domains in the nucleus. Two sub-pathways of NER remove UV-induced photolesions: (I) Global Genome Repair (GGR) and (II) Transcription Coupled Repair (TCR). GGR is a random process that occurs slowly, while the TCR, which is tightly linked to RNA polymerase II transcription, is highly specific and efficient. The efficiency of these pathways is important in avoiding cancer and genomic instability. Studies with cell lines derived from Cockayne syndrome (CS) and Xeroderma pigmentosum (XP) group C patients, that are defective in the NER sub-pathways, have yielded valuable information regarding the genomic heterogeneity of DNA repair. This review deals with the complexity of repair heterogeneity, its mechanism and interacting molecular pathways as well as its relevance in the maintenance of genomic integrity.