Smooth brome (Bromus inermis) is an introduced, cool-season perennial, sod-forming grass that has been shown to invade both native cool-and warm-season grasslands throughout North America. During the fall of 2005 through spring 2007, we implemented a smooth brome removal study at five sites in eastern South Dakota. Sites were selected to represent a range of soil and environmental conditions. Seven fall herbicide treatments, five spring herbicide treatments, an untreated plot that was planted with a native seed mix, and an untreated control that received no herbicide or seed addition were applied at each location in fall 2005/spring 2006 and fall 2006/spring 2007. Based upon first-year results, three fall herbicide treatments and two spring herbicide treatments were added in fall 2006/spring 2007. Sites were seeded with a native plant mix within 2 wk following spring herbicide treatment. Smooth brome cover in untreated plots ranged from 73 to 99% at the conclusion of the study. Smooth brome cover on herbicide-treated plots ranged from 0 to 84% on 2005/2006 plots and 0 to 98% on 2006/2007 plots after three growing seasons. Native plant response varied by site and treatment, possibly due to competition from exotic weeds. Although several herbicides show promise for control of smooth brome, future response of native plants will be important in determining the proper timing and herbicide combination.