Over the past 30 years, numerous reports on herbicide resistance have been published. Although research in this area is still in its infancy compared to the research done on insecticide and fungicide resistance, there are now more than 80 different plant species worldwide that have developed resistance to one or more herbicides. Mechanisms of herbicide resistance include metabolic detoxification, structural changes in the herbicide’s target site, alterations in the uptake, translocation, or compartmentalization of a herbicide. Although all of these modifications resulting in herbicide resistance in plants have been documented, alteration in the target site is the most common one and provides the highest level of resistance. Resistance has been shown to occur against all major herbicide classes. This chapter will review resistance to all major groups of herbicides, based on mode of action. The appearance of resistance is most likely in monoculture situations in which a herbicide or herbicides with the same mode of action are used continuously. One alarming trend is the emergence of weed species with resistance to herbicides with more than one site of action. This can occur as a result of either some mechanism of metabolic detoxification which degrades many herbicides or alterations in different herbicide target sites, or some combination of both of these mechanisms. Since the world has become very much dependent on herbicides for keeping weeds under control, additional reports on herbicide resistance are urgently needed.