Many genotoxic carcinogens are known to leave unique signatures on cancer-related genes. The signature of carcinogens is manifested by the induction of characteristic mutations at distinctive nucleotide positions along oncogenes and/or tumor suppressor genes. Often, the nucleotide positions, wherein mutations occur, co-localize with the sites of initial DNA damage induced by the respective carcinogens. Thus, DNA damage-targeted mutation can be a predictor of carcinogenicity of genotoxins. Today, genomic sequencing technologies for investigating human cancer etiology are based on DNA-lesion footprinting in conjunction with mutagenicity analysis of genotoxic carcinogens. In this review article, we discuss the ligation-mediated PCR and terminal transferase-dependent-PCR, two versatile DNA-lesion footprinting techniques. We highlight the in vitro shuttle vector-based mutation systems for investigating site-specific mutagenicity of carcinogens and the in vivo transgenic rodent mutation systems for exploring DNA damaging and mutagenic properties of carcinogens. We present examples of application of each of these methodologies to human cancer etiology, and provide prospective views on investigations using these technologies for carcinogenicity testing.