Technical Abstract: The relatively weak effort to use natural compounds as pesticide leads has lead to several commercial herbicides, including glufosinate, bialaphos, the triketones, and pelargonic acid. Furthermore, natural phytotoxins have often been found to have molecular target sites that were previously unknown as viable sites for herbicides. Commercially available herbicides target only about 20 enzymes or energy transfer processes. Even if the natural compound is not a competitive herbicide, the knowledge of a new target site can be used to develop herbicides with novel modes of action (1). This is even more important since the U.S. Food Quality Protection Act has combined food tolerance levels of pesticides with the same molecular target sites. Natural products have not been an area of focus for discovery efforts because of: the relatively high cost of bioassay-directed isolation, the probability of rediscovery, the often prohibitively complex structure of the active molecule, and the often more uncertain legal aspects of a patent. Furthermore, the approaches for discovery of natural product-based pesticide discovery are different from those for synthetic compounds, requiring a different laboratory infrastructure, including emphasis on natural product chemistry, rather than synthetic chemistry. The time and effort required for natural product-based herbicide discovery programs has been reduced by new methods, including semi-automated bioassays, automated chemical extraction and analysis, and molecular biology methods to probe biosynthesis and mode of action. We will focus on our own work in this area in this short review.