High-resolution mass spectrometry (HRMS) methods applying suspect screening and non-target analysis (NTA) approaches are becoming more commonly applied for the characterization of chemicals of emerging concern in a wide range of environmental and human matrices. They are particularly useful in extending our understanding of relevant contaminants by significantly expanding the range of chemicals we can assess beyond the limited target analysis and increasing representativeness of chemical exposure assessments. However, standardized methods for the application of HRMS-NTA approaches are not yet commonplace and large variability can exist between researchers and methods used. The typically extensive and information-rich datasets generated from these methods necessitate often elaborate strategies for processing and interpretation. Because of the complex datasets, challenges arise with ensuring reproducibility of results, especially if only considering quality control and assurance practices currently applied to target analytical methods. NTA requires a careful consideration of quality assurance and quality control (QA/QC) procedures and implementations across the analytical workflow (i.e., from sample collection and preparation through analysis and data acquisition to data processing and reporting). This chapter concerns the application of QA/QC strategies in NTA experiments and analysis and provides an overview of the fundamentals to be considered when considering NTA approaches. Rather than repeating some in-depth strategies that have already been highlighted in other works, this chapter summarizes the QA/QC steps to consider across the NTA workflow. A series of recommendations are highlighted, aiming at improving the standardization of quality assurance in NTA workflows.