Saflufenacil (Kixor™) is a new protoporphyrinogen IX oxidase (PPO) inhibiting herbicide for preplant burndown and selective PRE dicot weed control in multiple crops, including corn. The biokinetic properties and the mechanism of selectivity of saflufenacil in corn, black nightshade, and tall morningglory were investigated. After root treatment of plants at the third-leaf stage, the difference in the phytotoxic selectivity of saflufenacil in corn and the weed species has been quantified as approximately 10-fold. The plant species showed similar selectivity after foliar applications; the plant response to saflufenacil was approximately 100-fold more sensitive compared with a root application. PPO enzyme activity in vitro was inhibited by saflufenacil, a 50% inhibition lay in a concentration range from 0.2 to 2.0 nM, with no clear differences between corn and the weed species. Treatments of light-grown plants and dark-grown seedlings with [14C]saflufenacil revealed that the herbicide is rapidly absorbed by root and shoot tissue. The [14C]saflufenacil was distributed within the plant systemically by acropetal and basipetal movement. Systemic [14C]saflufenacil distribution can be explained by the weak acid character of saflufenacil and its metabolic stability in black nightshade and tall morningglory. Metabolism of [14C]saflufenacil in corn was more rapid than in the weeds. In addition, low translocation of root-absorbed [14C]saflufenacil in the corn shoot was observed. It is concluded that rapid metabolism, combined with a low root translocation, support PRE selectivity of saflufenacil in corn.