Intensive glyphosate use has contributed to the evolution and occurrence of glyphosate-resistant weeds that threaten production of many crops. Sustained use of this highly valued herbicide requires rotation and/or substitution of herbicides with different modes of action. Cotton growers have shown considerable interest in the protoporphyrinogen oxidase inhibitor, fomesafen. Following registration for cotton in 2008, use has increased rapidly. Environmental fate data in major use areas are needed to appropriately evaluate risks. Field-based rainfall simulation was used to evaluate fomesafen runoff potential with and without irrigation incorporation in a conventional tillage system (CT) and when conservation tillage (CsT) was practiced with and without cover crop residue rolling. Without irrigation incorporation, relatively high runoff, about 5% of applied, was measured from the CT system, indicating that this compound may present a runoff risk. Runoff was reduced by >50% when the herbicide was irrigation incorporated after application or when used with a CsT system. Data indicate that these practices should be implemented whenever possible to reduce fomesafen runoff risk. Results also raised concerns about leaching and potential groundwater contamination and crop injury due to rapid washoff from cover crop residues in CsT systems. Further work is needed to address these concerns.