In recent decades, advances have been made in the processes used to identify substances as persistent, bioaccumulative, and toxic (PBT). Key processes have been identified, and scientifically sound assessment methods have been developed. Regulatory agencies around the world have sought practical methods for implementing policies to protect both environment and human health. In the present paper, we review the various contributions that Mackay (in collaboration with his students and colleagues) has made to the development of scientifically sound methods for the identification of PBT substances and persistent organic pollutants. These contributions include efforts to clearly define the terminology and to develop scientifically defensible assessment models and evaluation frameworks.