This article summarizes discussions at the SETAC Pellston Workshop on “Science-Based Guidance and Framework for the Evaluation and Identification of PBTs and POPs” and provides an overview of other articles from that workshop that are also published in this issue. Identification of persistent, bioaccumulative, and toxic substances (PBTs) and persistent organic pollutants (POPs) and evaluation of their impact are more complicated than those for other chemicals and remain a challenge. The main reason for this is that PBT substance and POP assessment is associated with higher uncertainty and generally requires more data. However, for some data-rich PBTs and POPs, that identification and assessment of impact are feasible has been clearly demonstrated. New scientific developments and techniques are able to significantly increase the certainty of the various elements of PBT and POP assessment, and the current scientific literature provides many successful and illustrative examples that can be used as methodologies to build on. Applying multiple approaches for assessment is advisable, because it will reduce uncertainty and may increase confidence and improve the quality of decision-making.