Abstract BACKGROUND Understanding and managing the evolutionary responses of pests and pathogens to control efforts is essential to human health and survival. Herbicide‐resistant ( HR ) weeds undermine agricultural sustainability, productivity and profitability, yet the epidemiology of resistance evolution – particularly at landscape scales – is poorly understood. We studied glyphosate resistance in a major agricultural weed, Amaranthus tuberculatus (common waterhemp), using landscape, weed and management data from 105 central Illinois grain farms, including over 500 site‐years of herbicide application records. RESULTS Glyphosate‐resistant ( GR ) A. tuberculatus occurrence was greatest in fields with frequent glyphosate applications, high annual rates of herbicide mechanism of action ( MOA ) turnover and few MOAs field −1 year −1 . Combining herbicide MOAs at the time of application by herbicide mixing reduced the likelihood of GR A. tuberculatus . CONCLUSIONS These findings illustrate the importance of examining large‐scale evolutionary processes at relevant spatial scales. Although measures such as herbicide mixing may delay GR or other HR weed traits, they are unlikely to prevent them. Long‐term weed management will require truly diversified management practices that minimize selection for herbicide resistance traits. © 2015 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.