Patrick J Tranel

The emergence of herbicide‐resistant weeds is a significant threat to modern agriculture. Cross resistance, a phenomenon where resistance to one herbicide confers resistance to another, is a particular concern owing to its unpredictability. Nontarget‐site (NTS) cross resistance is especially challenging to predict, as it arises from genes that encode enzymes that do not directly involve the herbicide target site and can affect multiple herbicides. Recent advancements in genomic and structural biology techniques could provide new venues for predicting NTS resistance in weed species. In this review, we present an overview of the latest approaches that could be used. We discuss the use of genomic and epigenomics techniques such as ATAC‐seq and DAP‐seq to identify transcription factors and cis‐regulatory elements associated with resistance traits. Enzyme/protein structure prediction and docking analysis are discussed as an initial step for predicting herbicide binding affinities with key enzymes to identify candidates for subsequent in vitro validation. We also provide example analyses that can be deployed toward elucidating cross resistance and its regulatory patterns. Ultimately, our review provides important insights into the latest scientific advancements and potential directions for predicting and managing herbicide cross resistance in weeds. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.