This chapter considers herbicide activation and detoxication, and intrinsic differences in sensitivity at the site(s) of action. Metabolism resulting in detoxication is an effective mechanism for reducing the toxic concentration of the herbicide and increasing the plant's tolerance toward the chemical. The basic biochemical reactions in higher plants that generally result in herbicide detoxication are oxidation, reduction, hydrolysis, and conjugation. Oxidation reactions of herbicides are most common in plants and frequently are primary reactions that result in either detoxication or activation of the herbicide. Conjugation is a major mechanism in herbicide detoxication and selectivity in plants. Conjugation increases the polarity of the herbicide or its metabolite; thus making the conjugated metabolite extremely difficult to isolate, purify and characterize. Glutathione conjugation is recognized as a major herbicide detoxication pathway in plants. Aryl hydroxylation of herbicides is generally assumed to be a detoxication reaction.