The US Great Plains comprise the major cereal producing states in the country. In the US, wheat (winter and spring wheat) was grown in 45 million acres in 2014, with a total production of 55 M metric tons. Wheat after chemical fallow (W-F) dominates > 90% of the dryland cropping systems of the Northern Great Plains of the US, where soil moisture (< 300 mm of average annual precipitation) is often the limiting factor for continuous cropping. In the Central Great Plains of the US, wheat–corn/grain sorghum–fallow (W-C/G-F) is a common dryland rotation. An over-reliance on herbicides for weed control in these no-till cropping systems has resulted in weed shifts and escalated cases of resistance evolution in weed populations to single or multiple site-of-action herbicides. Early detection, increased awareness of socio-economic implications of herbicide-resistant weeds, and adoption of diversified weed control tactics would mitigate the further evolution of multiple herbicide-resistant weed biotypes in cereal production systems.