Genomic DNA is damaged by a variety of factors exerting an adverse effect on human health, such as environmental pollution, UV light, ionizing radiation, and toxic compounds. Air pollution with products of incomplete combustion of hydrocarbon fuels and wastes of various industries are main sources of polycyclic aromatic hydrocarbons, whose metabolites can damage DNA by forming bulky DNA adducts, which potentially lead to mutations and cancer. Nucleotide excision repair is the main pathway that eliminates these lesions in eukaryotic cells. The excision efficiency of bulky adducts depends on many factors, including the structure of a bulky substituent and the degree of DNA double helix distortion induced by a lesion. Clustered DNA lesions are the most dangerous for the cell. Several DNA repair systems cooperate to recognize and remove such lesions. The review focuses on the mechanisms that repair DNA with single and clustered bulky lesions, taking the natural carcinogen benzo[a]pyrene as an example.