This symposium builds upon a 2018 PittCon symposium I organized that covered different approaches for non-targeted and suspect screening methods using high-resolution mass spectrometry to identify unknowns. Non-targeted analysis differs from traditional chemical methods by not using a predefined list of compounds to screen against. Suspect screening is a complementary approach where a large list of compounds is used to aid in identifying known hazards or adulterants by using exact mass. Implementation of these methods has skyrocketed and been applied in many diverse research fields including, but not limited to, forensic analysis, discovering the presence of contaminants and adulterants to ensure food safety, identifying markers for disease with metabolomics, and determining potential hazards for environmental analysis. These methods are incredibly powerful but can be complicated and vary greatly. Thousands of different chemicals from many chemical classes can be detected, which makes it challenging to apply standard analytical practices to demonstrate that these methods are fit-for-purpose. In this session, I would like to focus on considerations and best practices for implementing these types of analyses and emerging approaches.