Protoporphyrinogen oxidase (PPO) inhibiting herbicides remain an important and useful chemistry 60 years after their first introduction. In this review, based on topics introduced at the WSSA 2021 symposium titled “A History, Overview, and Plan of Action on PPO Inhibiting Herbicides”, we discuss the current state of PPO inhibiting herbicides. Renewed interest in the PPO inhibiting herbicides in recent years, due to increased use and increased resistance cases, has led to refinements in knowledge regarding the mechanism of action of PPO inhibitors. Herein we discuss the importance of the two isoforms of PPO in plants, compile a current knowledge of target site resistance mechanisms, discuss non target site resistance cases and review crop selectivity mechanisms. To effectively study and compare PPO inhibitor resistance cases, consistent and reproducible greenhouse screening and target site mutation assays are necessary. To this end we cover best practices in screening to accurately identify resistance ratios and properly interpret common screens for point mutations. The future of effective and sustainable PPO inhibitor use relies on development of new chemistries that maintain activity on resistant biotypes and the promotion of responsible stewardship of PPO inhibitors both new and old. We present the biorational design of the new PPO inhibitor trifludimoxazin to highlight the future of PPO inhibitor development and discuss the elements of sustainable weed control programs using PPO inhibitors as well as how responsible stewardship can be incentivized. The sustained use of PPO inhibitors in future agriculture relies on the effective and timely communication from mode of action and resistance research to agronomists, extension workers, and farmers themselves.