Herbicides have been placed in global Herbicide Resistance Action Committee (HRAC) herbicide groups based on their sites of action (e.g., acetolactate synthase–inhibiting herbicides are grouped in HRAC Group 2). A major driving force for this classification system is that growers have been encouraged to rotate or mix herbicides from different HRAC groups to delay the evolution of herbicide-resistant weeds, because in theory, all active ingredients within a herbicide group physiologically affect weeds similarly. Although herbicide resistance in weeds has been studied for decades, recent research on the biochemical and molecular basis for resistance has demonstrated that patterns of cross-resistance are usually quite complicated and much more complex than merely stating, for example, a certain weed population is Group 2-resistant. The objective of this review article is to highlight and describe the intricacies associated with the magnitude of herbicide resistance and cross-resistance patterns that have resulted from myriad target-site and non–target site resistance mechanisms in weeds, as well as environmental and application timing influences. Our hope is this review will provide opportunities for students, growers, agronomists, ag retailers, regulatory personnel, and research scientists to better understand and realize that herbicide resistance in weeds is far more complicated than previously considered when based solely on HRAC groups. Furthermore, a comprehensive understanding of cross-resistance patterns among weed species and populations may assist in managing herbicide-resistant biotypes in the short term by providing growers with previously unconsidered effective control options. This knowledge may also inform agrochemical company efforts aimed at developing new resistance-breaking chemistries and herbicide mixtures. However, in the long term, nonchemical management strategies, including cultural, mechanical, and biological weed management tactics, must also be implemented to prevent or delay increasingly problematic issues with weed resistance to current and future herbicides.