Trends in LC/GC‐HRMS Non‐Targeted Screening of Unknown Contaminants of Emerging Concern in Aquatic Systems: Workflows, No‐Standard Identification, and Environmental Applications

Non‐targeted screening (NTS) coupled with high‐resolution mass spectrometry (HRMS) has revolutionized detection of unknown contaminants of emerging concern (CECs), including pharmaceutical transformation products, novel disinfection byproducts, emerging PFAS variants, and a wide diversity of other organic micropollutants, without reliance on reference standards. This critical review focuses on aquatic matrices (wastewater, surface water, drinking water, and related environmental waters) and examines current trends in LC‐HRMS and GC‐HRMS workflows, highlighting their complementarity for comprehensive chemical‐space coverage in complex environmental matrices. Principal advances include generic sample preparation strategies, advanced data processing tools (MZmine, patRoon, Compound Discoverer), Schymanski et al.‐based identification frameworks with recent harmonization efforts, and the integration of suspect‐enhanced non‐target approaches. Complementary LC/GC workflows, enhanced by ion mobility and multi‐dimensional separations, significantly improve feature detection and identification confidence for unknowns. The review further explores the translation of NTS data into risk‐assessment frameworks via effect‐directed and virtual EDA approaches, as well as selected applications in wastewater‐based epidemiology (WBE). Key challenges persist, including high data volume and complexity, false positives/negatives, matrix effects, semi‐quantification uncertainty, and limited inter‐laboratory reproducibility. Recent harmonization initiatives by the NORMAN network and interlaboratory studies are progressively addressing these gaps through standardized QA/QC and reporting practices. In conclusion, LC/GC‐HRMS NTS offers transformative potential for early‐risk detection and proactive regulatory decision‐making, particularly in the context of expanding EPA PFAS monitoring. Future perspectives emphasize AI‐driven automation, multi‐omics integration, real‐time monitoring platforms, and stronger linkage to policy frameworks. As harmonization and technological advances mature, NTS will shift environmental analysis from reactive targeted monitoring toward predictive, systems‐level protection of human and ecological health.