Natural grasslands are one of the most threatened ecosystems in North America. Conservation efforts are often hampered by exotic plant invasions in existing remnant natural grasslands. Tall fescue [Schedonorus phoenix (Scop.) Holub.] is an introduced cool-season (C3) forage/turf grass which readily invades natural grasslands in Kentucky and neighboring states. Our study objectives were to (1) compare the efficacy and application timing effect of clethodim to that of imazapic to selectively remove tall fescue from natural grasslands and (2) evaluate the response of the nontarget grassland plant community (i.e., native grass and forb canopy cover) following herbicide treatments. Clethodim and imazapic treatments consisted of early (April 4, 2001) and late (April 20, 2001) applications, and these were applied at 0.23 and 0.21 kg ai ha−1, respectively. Both herbicides reduced tall fescue cover (P ≤ 0.05); herbicide application timing had no effect on herbicide efficacy to control tall fescue. Native grass cover was higher (P ≤ 0.05) in all herbicide-treated plots compared to the untreated controls, except for the late clethodim-treated plots. All herbicide treatments increased forb abundance compared to controls. Spring applications of clethodim were equally effective to those of imazapic at controlling tall fescue in natural grasslands. Imazapic released native grasses better than clethodim, whereas clethodim was better at increasing forb abundance. Furthermore, early clethodim treatments had fewer nontarget effects on native C4 grasses compared to late clethodim treatments. Overall, clethodim shows promise as a beneficial management tool for tall fescue control in C4-dominated natural grasslands.