Exposomics refers to the comprehensive analysis of environmental exposures over the lifespan and assessment of their biological effects on human health. This new frontier in environmental research promises new insights for assessment of the hazards of complex chemical exposures as compared to targeted biomonitoring of a limited panel of known toxicant(s). Metabolomics plays a pivotal role in expanding exposomic initiatives that require orthogonal separation methods coupled to high-resolution mass spectrometry while using minimally invasive specimens from prospective cohort studies that can capture early life exposures. However, several grand analytical challenges remain, including high-throughput metabolomic data workflows that are scalable to large populations, the identification of unknown contaminants and their contact sources, and elucidating the impact of multiple co-exposures at critical stages of development. In this review, we outline new advances in metabolomic technologies for exposomics research over the past five years that are urgently needed to guide regulatory policies via better exposure mitigation and strategies to improve metabolic resilience.