Modern herbicides make major contributions to global food production by easily removing weeds and substituting for destructive soil cultivation. However, persistent herbicide selection of huge weed numbers across vast areas can result in the rapid evolution of herbicide resistance. Herbicides target specific enzymes, and mutations are selected that confer resistance-endowing amino acid substitutions, decreasing herbicide binding. Where herbicides bind within an enzyme catalytic site very few mutations give resistance while conserving enzyme functionality. Where herbicides bind away from a catalytic site many resistance-endowing mutations may evolve. Increasingly, resistance evolves due to mechanisms limiting herbicide reaching target sites. Especially threatening are herbicide-degrading cytochrome P450 enzymes able to detoxify existing, new, and even herbicides yet to be discovered. Global weed species are accumulating resistance mechanisms, displaying multiple resistance across many herbicides and posing a great challenge to herbicide sustainability in world agriculture. Fascinating genetic issues associated with resistance evolution remain to be investigated, especially the possibility of herbicide stress unleashing epigenetic gene expression. Understanding resistance and building sustainable solutions to herbicide resistance evolution are necessary and worthy challenges.