Research was conducted from 2011 to 2015 to determine the effect of herbicide strategy on efficacy and evolution of herbicide resistance in weeds in a continuous glyphosate- and dicamba-resistant (GDr) soybean system. The nine herbicide strategies included sequential applications of glyphosate only, glyphosate plus dicamba with or without acetochlor, PRE application of residual herbicides with POST glyphosate or non-glyphosate herbicides, and their biennial rotation with one another. Giant foxtail and horseweed were the least problematic during all growing seasons. An increase in horseweed was observed by the end of the experiment especially in the plots where POST glyphosate was not used with PRE application of residual herbicides. Giant ragweed evolved resistance to glyphosate over a 4-yr period of selection with strategies that predominantly included PRE and POST glyphosate. Herbicide use strategies that included glyphosate-only and PRE application of residual herbicides fb POST glyphosate annually or in a biennial rotation were ineffective in controlling giant ragweed and glyphosate-resistant (GR) common waterhemp. Over the years, application of PRE herbicide mixtures before POST glyphosate application improved weed control and soybean yields compared with the glyphosate-only strategy. During all growing seasons, the greatest yield and reduction in total weed density before harvest was provided by herbicide use strategies that included glyphosate plus dicamba annually or in a biennial rotation regardless of the inclusion of acetochlor POST. Dicamba proved to be a valuable addition to improve the control of GR weeds. GDr soybean will provide growers with a new option for managing resistant weeds, but it needs to be used with caution, as multiple resistance in weeds, including waterhemp and giant ragweed, is already widespread.