Farmers in southern Ontario face a significant threat from glyphosate-resistant weeds such as Canada fleabane and giant ragweed. Left uncontrolled, glyphosate-resistant weed interference in soybean can result in substantial yield loss. The three objectives of this study were: 1) to determine the biologically effective rate of isoxaflutole, metribuzin, and glyphosate on glyphosate-resistant Canada fleabane and giant ragweed biotypes, 2) to assess the response of isoxaflutole and glyphosate applied as a tank-mix on glyphosate-resistant and glyphosate-susceptible biotypes of both species, and 3) to ascertain the response of isoxaflutole, metribuzin and glyphosate tank-mix on the glyphosate-resistant biotypes of both species. In growth room experiments, antagonism is observed at low rates of glyphosate plus isoxaflutole in glyphosate-susceptible giant ragweed and at field rates of the same tank-mix in glyphosate-resistant Canada fleabane. The addition of metribuzin to the tank-mix resulted in an additive or synergistic response across all rates in the glyphosate-resistant biotypes of both species tested. Field experiments confirmed the additive and synergistic response of the three-way tank-mix in both species tested. An estimated 631 (126+504) and 420 (84+336) g a.i. ha-1 of isoxaflutole plus metribuzin in a 1:4 ratio are required for control of glyphosate-resistant giant ragweed and Canada fleabane respectively.