Trichloroethylene (TCE), an organic solvent commonly used for metal degreasing and as a chemical additive, is a significant environmental contaminant that poses health concerns in humans. The US Environmental Protection Agency (EPA) is currently revising the 2001 TCE human risk assessment draft. The next draft is expected to be ready in 2008. TCE metabolites are detectable in humans and carry varying potencies for induction of cancers in animals. Genomic mechanisms have been explored in animals and humans to link TCE to carcinogenesis. DNA analysis provides an opportunity for detection of unique genetic alterations representing a signature of TCE exposure. These alterations can arise from genotoxic and nongenotoxic pathways at multiple points throughout tumorigenesis. Although fixation of alterations may require several stages of selection and modification, the spectra can be specific to TCE. Only a fraction of these alterations eventually lead to tumor formation and some contribute to tumor progression. Genetic events in two major TCE target organs are reviewed, including the VHL gene in kidney, and the Ras gene and genome-wide hypomethylation in liver. Attempts to identify a genetic signature of TCE exposure are challenged by inconsistent findings, lack of evidence of promutagenic lesions, biological relevance of specific genomic changes, and likelihood of coexposures. For human risk assessment, genome-wide screening is useful and is possible with the development of new DNA-sequencing technologies. Genetic screening for preneoplastic and tumor tissues from high-risk population is proposed to exclude the noise of passenger mutations and genetic polymorphisms.