Processing (eg, cooking, grinding, drying) has changed the composition of food throughout the course of human history; however, awareness of process-formed compounds, and the potential need to mitigate exposure to those compounds, is a relatively recent phenomenon. In May 2015, the North American Branch of the International Life Sciences Institute (ILSI North America) Technical Committee on Food and Chemical Safety held a workshop on the risk-based process for mitigation of process-formed compounds. This workshop aimed to gain alignment from academia, government, and industry on a risk-based process for proactively assessing the need for and benefit of mitigation of process-formed compounds, including criteria to objectively assess the impact of mitigation as well as research needed to support this process. Workshop participants provided real-time feedback on a draft framework in the form of a decision tree developed by the ILSI North America Technical Committee on Food and Chemical Safety to a panel of experts, and they discussed the importance of communicating the value of such a process to the larger scientific community and, ultimately, the public. The outcome of the workshop was a decision tree that can be used by the scientific community and could form the basis of a global approach to assessing the risks associated with mitigation of process-formed compounds.