Herbicide-resistant populations have evolved only in monoculture and/or monoherbicide conditions at predictable rates for each compound and weed. No populations of triazine-resistant weeds have appeared in corn where rotations of crops and herbicides or herbicide mixtures were used. This is due to the greatly reduced competitive fitness of the resistant individuals, which could be expressed only during rotational cycles, and also to the greater sensitivity of resistant individuals to other herbicides, pests, and control practices (“negative cross-resistance”). The model presented here describes how an understanding of all of these factors can provide strategies to decrease the frequency of the resistant individuals during rotation. Rotations or mixtures may not delay the rate of appearance of resistance to inhibitors of acetolactate synthase (ALS), where the fitness of resistant biotypes is claimed to be near normal. The best way to delay resistance to ALS inhibitors is to use those compounds with less persistence so that the selection pressure will be lowered. Too little is known about the frequency of resistance to other herbicides with target-site resistance–to dinitroanilines, to acetyl CoA carboxylase inhibitors, or to those situations where a single enzyme system confers resistance to a broad spectrum of seemingly unrelated herbicides.