As the demand for safer chemicals and technologies grows, the field of alternatives assessment is becoming increasingly important in guiding the transition towards safer, less toxic alternatives. While the use and practice of alternatives assessment approaches have advanced considerably in the last decade, important gaps in alternatives assessment approaches remain. A major limitation that can hinder efforts to evaluate and adopt alternatives for priority chemicals is the lack of consistent criteria for defining “safer.” Practitioners face challenges on what constitutes “safer” when evaluating alternatives from both a hazard and exposure perspective. This guidance aims to identify and outline key considerations for the identification and selection of safer alternatives. It is intended to advance a consistent understanding of the minimum requirements needed to determine whether a chemical alternative is safer than the priority chemical, product, or technology for substitution, independent of the entity performing the assessment or the alternatives assessment framework being used.