Roundup Ready (glyphosate-resistant) cropping systems enable the use of glyphosate, a non-selective herbicide that offers growers several benefits, including superior weed control, flexibility in weed control timing and economic advantages. The rapid adoption of such crops in North America has resulted in greater glyphosate use and concern over the potential for weed resistance to erode the sustainability of its efficacy. Computer modeling is one method that can be used to explore the sustainability of glyphosate when used in glyphosate-resistant cropping systems. Field tests should help strengthen the assumptions on which the models are based, and have been initiated for this purpose. Empirical evaluations of published data show that glyphosate-resistant weeds have an appearance rate of 0.007, defined as the number of newly resistant species per million acres treated, which ranks low among herbicides used in North America. Modeling calculations and ongoing field tests support a practical recommendation for growers occasionally to include other herbicides in glyphosate-resistant cropping systems, to lower further the potential for new resistance to occur. The presented data suggest that the sustainability of glyphosate in North America would be enhanced by prudent use of additional herbicides in glyphosate-resistant cropping systems.