Herbicides targeting grass plastidic acetyl coenzyme A carboxylase (ACC) are effective selective graminicides. Their intensive use worldwide has selected for resistance genes in a number of grass weed species. Biochemistry and molecular biology have been the means of determining the herbicidal activity and selectivity toward crop plants of ACC-inhibiting herbicides. In recent years, elucidation of the tridimensional structure of ACC and identification of five amino acid residues within the ACC carboxyl transferase domain that are critical determinants for herbicide sensitivity shed light on the basis of ACC-based resistance to herbicides. However, metabolism-based resistance to ACC-inhibiting herbicides is much less well known, although this type of resistance seems to be widespread. A number of genes thus endow resistance to ACC-inhibiting herbicides, with the possibility for various resistance genes that confer dominant resistance at the herbicide field rate to accumulate within a single weed population or plant. This, together with a poor knowledge of the genetic parameters driving resistance, renders the evolution of resistance to ACC-inhibiting herbicides unpredictable. Future research should consider developing tactics to slow the spread of resistance. For this purpose, it is crucial that our understanding of metabolism-based resistance improves rapidly because this mechanism is complex and can confer resistance to herbicides with different target sites.