Exposomics seeks a comprehensive understanding of the links between human health and environmental chemical exposures. Analytical chemistry tools capable of identifying low-level organic contaminants in complex environmental samples are needed to meet the demands of exposomics studies. High-resolution accurate-mass mass spectrometry (HR/AM MS) and nontargeted analysis currently provide the only framework capable of achieving the sensitivity, specificity, and throughput required by large-scale exposomics studies. However, practical tools for the automated and reproducible structure annotation of small molecules by HR/AM MS remain underdeveloped. Herein, we review the principles of and recent advances in HR/AM MS–enabled nontargeted analysis with an emphasis on approaches to assigning chemical information to HR/AM MS data.