Nucleotide excision repair is a cut-and-patch pathway that eliminates potentially mutagenic DNA lesions caused by ultraviolet light, electrophilic chemicals, oxygen radicals and many other genetic insults. Unlike antigen recognition by the immune system, which employs billions of immunoglobulins and T-cell receptors, the nucleotide excision repair complex relies on just a few generic factors to detect an extremely wide range of DNA adducts. This molecular versatility is achieved by a bipartite strategy initiated by the detection of abnormal strand fluctuations, followed by the localization of injured residues through an enzymatic scanning process coupled to DNA unwinding. The early recognition subunits are able to probe the thermodynamic properties of nucleic acid substrates but avoid direct contacts with chemically altered bases. Only downstream subunits of the bipartite recognition process interact more closely with damaged bases to delineate the sites of DNA incision. Thus, consecutive factors expand the spectrum of deleterious genetic lesions conveyed to DNA repair by detecting distinct molecular features of target substrates.