The recent advances of novel methodologies such as non-targeted and suspect screening based on high-resolution mass spectrometry (HRMS) have paved the way to a new paradigm for exposure assessment. These methodologies allow to profile simultaneously thousands of small unknown molecules present in environmental and biological samples, and therefore hold great promises in order to identify more efficiently hazardous contaminants potentially associated with increased risks of developing adverse health outcomes. In order to further explore the potential of these methodologies and push the transition from research applications towards regulatory purposes, robust harmonized quality standards have to be implemented. Here, we discuss the feasibility of using ISO/IEC 17025: 2017 as a guideline to implement non-targeted and suspect screening methodologies in laboratories, whether it is for accreditation purposes or not. More specifically, we identified and then discussed how specificities of non-targeted HRMS methodology can be accounted for in order to comply with the specific items of ISO/IEC 17025: 2017. We also discussed other specificities of HRMS methodologies (e.g., need for digital storage capacity) that are so far not included in the ISO/IEC 17025 requirements but should be considered. This works aims to fuel and expand the discussion in order to subsidize new opportunities of harmonization for non-targeted and suspect screening.