Technical Abstract: New mechanisms of action for herbicides are highly desirable to fight evolution of resistance in weeds, to create or exploit unique market niches, and to cope with new regulatory legislation. Comparison of the known molecular target sites of synthetic herbicides and natural phytotoxins reveals that there is little redundancy. Comparatively little effort has been expended on determination of the sites of action of phytotoxins from natural sources, suggesting that intensive study of these molecules will reveal many more novel mechanisms of action. Examples of natural products that inhibit unexploited steps in the amino acid, nucleic acid, and other biosynthetic pathways are given. AAL-toxin, hydantocidin, and various plant-derived terpenoids are discussed. Strategies and potential pitfalls of using natural products as leads for new herbicide classes are summarized.