Globally, reported cases of herbicide-resistant weeds have been increasing at a nearly linear rate since 1980, with more than 11 new cases each year. Some herbicides are more prone to resistance evolution than others, but no herbicide is immune to this process. Currently, 21 weed species have evolved resistance to glyphosate, the most heavily relied upon herbicide in the world. Those species that have evolved resistance to glyphosate tend to be among the most problematic weeds. In particular, many of the same species that have evolved glyphosate resistance had previously evolved resistance to herbicides from other mode-of-action groups. Furthermore, it is becoming increasingly common for weed populations – and even individual plants – to have multiple resistance. As more and more herbicide-resistance traits become “stacked” within weed populations, options for effective chemical control become severely limited. Waterhemp is a weed “close to home” that exemplifies the problem of multiple herbicide resistance. This species has evolved resistance to herbicides from five different mode-of-action groups. Many waterhemp populations now possess resistance to two or more herbicide groups, and at least one population possesses resistance to four different herbicide groups. Unfortunately, the dwindling number of effective herbicide options is a problem that will not go away anytime soon:  herbicides with new modes of action are unlikely to be commercialized in the near future. If we are to effectively manage weeds, we likely will need to become more site-specific with our management approach. Chemical and non-chemical weed management tactics will have to be tailored to each field, depending on the spectrum of weed species and resistant biotypes.