Herbicide-resistant weeds are a constraint to weed management in many cropping regions around the world. Of the numerous populations of weeds with resistance to herbicides, it appears that most have resistance due to an alteration to the target enzyme. Use of herbicides with alternative modes of action has relatively easily controlled these populations. In stark contrast are a much smaller number of populations with resistance due to increased rates of herbicide detoxification. These populations may be cross-resistant to herbicides with other modes of action. Such cross-resistance can severely compromise weed control because alternative herbicides may fail on their first use. It has proved extremely difficult to predict cross-resistance due to increased herbicide detoxification in weed populations and hence, difficult to provide adequate advice to growers on how to avoid or manage the problem. Most commonly, such cross-resistance has been selected by certain aryloxyphenoxypropanoate herbicides such as diclofop-methyl and phenylurea herbicides such as chlorotoluron and isoproturon; however, other herbicides can also act as selecting agents for this type of resistance. Illustrative examples from rigid ryegrass in Australia and blackgrass in Europe demonstrate the breadth of the problem and the magnitude of the effort required to understand increased herbicide detoxification as a resistance mechanism. Recent work has elucidated the genetic basis of cross-resistance in some populations, but this has so far not provided new predictive tools useful to growers. Despite more than a decade of research aimed at unraveling the complexities of cross-resistance due to increased herbicide detoxification, management of these cross-resistant populations remains a significant challenge.