AbstractStudies of mechanisms of resistance to glyphosate have increased current understanding of herbicide resistance mechanisms. Thus far, single‐codon non‐synonymous mutations of EPSPS (5‐enolypyruvylshikimate‐3‐phosphate synthase) have been rare and, relative to other herbicide mode of action target‐site mutations, unconventionally weak in magnitude for resistance to glyphosate. However, it is possible that weeds will emerge with non‐synonymous mutations of two codons of EPSPS to produce an enzyme endowing greater resistance to glyphosate. Today, target‐gene duplication is a common glyphosate resistance mechanism and could become a fundamental process for developing any resistance trait. Based on competition and substrate selectivity studies in several species, rapid vacuole sequestration of glyphosate occurs via a transporter mechanism. Conversely, as the chloroplast requires transporters for uptake of important metabolites, transporters associated with the two plastid membranes may separately, or together, successfully block glyphosate delivery. A model based on finite glyphosate dose and limiting time required for chloroplast loading sets the stage for understanding how uniquely different mechanisms can contribute to overall glyphosate resistance. © 2014 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.