Sulfur mustard (SM) is an extensive nucleophilic and alkylating agent that targets different tissues. The genotoxic property of SM is the most threatening effect, because it is associated with detrimental inflammations and susceptibility to several kinds of cancer. Moreover, SM causes a wide variety of adverse effects on DNA which result in accumulation of DNA adducts, multiple mutations, aneuploidies, and epigenetic aberrations in the genome. However, these adverse effects are still not known well, possibly because no valid biomarkers have been developed for detecting them. The advent of next-generation sequencing (NGS) has provided opportunities for the characterization of these alterations with a higher level of molecular detail and cost-effectivity. The present review introduces NGS approaches for the detection of SM-induced DNA adducts, mutations, chromosomal structural variation, and epigenetic aberrations, and also comparing and contrasting them with regard to which might be most advantageous.