The spinosyns are unique insecticidal secondary metabolites produced by two soil bacteria, Saccharopolyspora spinosa and S. pogona. Spinosad and spinetoram, the two active ingredients developed from the spinosyns, received Presidential Green Chemistry Challenge Awards in 1999 and 2008, respectively. Spinosad is derived entirely from fermentation, whereas spinetoram is created by making two synthetic modifications to fermentation-derived spinosyn starting materials. These modifications resulted from innovative approaches to quantify spinosyn structure-activity relationships, and the modifications make spinetoram more active and enable it to provide longer-lasting control than spinosad. The spinosyn mode of action involves a unique site on the nicotinic acetylcholine (nACh) receptor. Low toxicity to mammals and most other non-target species provides a wide margin of safety for agricultural workers and the environment. The spinosyns have short environmental persistence and degrade by physical and microbial processes into simpler fragments containing only carbon, oxygen, nitrogen, and hydrogen. Spinosyn insecticide manufacturing is a green, fermentation-based process using renewable agricultural feedstocks. The spinosyn insecticides have had a huge impact on agriculture by providing control of a broad range of important arthropod pests across more than 250 crops in more than 80 countries. Spinosad and spinetoram are generally compatible with Integrated Pest Management (IPM) programs. Spinosad's natural origin has enabled certification for organic agriculture in a growing number of countries, and it has significant noncrop uses in stored grain protection, animal health, and public health. Further research and advances in delivery systems technology will open an even wider range of uses for the spinosyns.