Glyphosate, N-(phosphonomethyl)glycine, is the most extensively used herbicide in the history of agriculture. Weed management programs in glyphosate resistant (GR) field crops have provided highly effective weed control, simplified management decisions, and given cleaner harvested products. However, this relatively simple, broad-spectrum, systemic herbicide can have extensive unintended effects on nutrient efficiency and disease severity, thereby threatening its agricultural sustainability. A significant increase in disease severity associated with the wide spread application of the glyphosate herbicide can be the result of direct glyphosate-induced weakening of plant defenses and increased pathogen population and virulence. Indirect effects of glyphosate on disease predisposition result from immobilization of specific micronutrients involved in disease resistance, reduced growth and vigor of the plant from accumulation of glyphosate in meristematic root, shoot, and reproductive tissues, altered physiological efficiency, or modification of the soil microflora affecting the availability of nutrients involved in physiological disease resistance. Strategies to ameliorate the predisposing effects of glyphosate on disease include judicious selection of herbicide application rates, micronutrient amendment, glyphosate detoxification in meristematic tissues and soil, changes in cultural practices to enhance micronutrient availability for plant uptake, and biological amendment with glyphosate-resistant microbes for nitrogen fixation and nutrient availability. Given that recommended doses of glyphosate are often many times higher than needed to control weeds, we believe the most prudent method to reduce the detrimental effects of glyphosate on GR crops will be to use this herbicide in as small a dose as practically needed. Such a frugal approach will not only curtail disease predisposition of GR crops, but will also benefit the grower and the environment.