Insects cope with environmental threats using a broad array of strategies. A key strategy, widespread among insects but unappreciated until recently, is the use of molecular defenses from symbiotic microbes. Insect-microbe defensive symbioses span the diversity of insect lineages and microbial partners and use molecules ranging from reactive oxygen species to small molecules to protein toxins to defend against predators, parasites, and microbial pathogens. These systems have a strong initial track record as sources of novel biologically active compounds with therapeutic potential. This review surveys the molecular basis for insect-microbe defensive symbioses with a focus on the ecological contexts for defense and on emerging lessons about molecular diversity from bacterial genomes.