While herbicides are the most effective and widely adopted weed management approach, the evolution of multiple herbicide resistance in damaging weed species threatens the yield and profitability of many crops. Weeds accumulate multiple resistance mechanisms through sequential selection and/or gene flow, with long-range and international transport of herbicide-resistant weeds proving to be a serious issue. Metabolic resistance mechanisms can confer resistance across multiple sites of action and even to herbicides not yet discovered. When a new site of action herbicide is introduced to control a key driver weed, it likely will be one of very few effective available herbicide options for that weed in a specific crop due to the continuous use of herbicides over the years and the resulting accumulation of resistance mechanisms, placing it at even higher risk to be rapidly lost to resistance due to the high selection pressure it will experience. The number of available, effective herbicides for certain driver weeds is decreasing over time because the rate of resistance evolution is faster than the rate of new herbicide discovery. Effective monitoring for species movement and diagnostics for resistance should be deployed to rapidly identify emerging resistance to any new site of action. While innovation in herbicide discovery is urgently needed to combat the pressing issue of resistance in weeds, the rate of selection for herbicide resistance in weeds must be slowed through changes in the patterns of how herbicides are used.