The significance of glyphosate and the appearance of glyphosate-resistant weeds have raised concerns about glyphosate sustainability. Resistance-prevention strategies, however, should first consider the mechanisms for resistance. For example, target-site resistance can provide virtual immunity, ensuring that every herbicide application successfully selects for resistance. However, metabolism and exclusion mechanisms provide lower magnitudes of resistance and are dependent on dosage. This discussion proposes that the relative risk of weed resistance is most highly correlated to mode of action (MOA), due to the respective principal mechanism for resistance. The development of data correlating agronomic practices with weed resistance vs. herbicide/MOA choices will be critical to the design of effective prevention strategies. Because resistance to glyphosate in weeds is typically of a low magnitude, using a high-dose strategy should minimize the potential for the selection of resistance and thus help to make the use of glyphosate sustainable. Maximizing weed control is the key to successful agronomic practice with limited weed resistance.