Although large size is considered an evolved antipredator defense for some vertebrates and shellfish, large size is generally not considered an adaptive defensive trait in insects. Here we propose that large size in chemically defended grasshoppers has evolved as a beneficial antipredator trait. The lubber grasshoppers Romalea microptera and Taeniopoda eques are the largest grasshoppers in North America north of Mexico. These closely related species escape most vertebrate predation by possessing powerful predator-deterrent toxins and by nocturnal roosting. We hypothesize that escape from vertebrate predation allowed lubbers to evolve a larger body size, increased fecundity and provided many other benefits, including defense against invertebrate predators. To test the hypotheses that large lubber size reduces predation, we conducted feeding trials with wolf spiders (Honga carolinensis), assassin bugs (Arilus cristatus), preying mantids (Tenodera aridifolia), fire ants (Solenopsis invicta), frogs (Rana pipiens), and birds (Sturnus vulgaris and Passer domesticus). Our results show that larger lubber instars enjoyed a highly significant advantage vis-à-vis predators, demonstrating the adaptive value of large size against both vertebrate and invertebrate predators. Adult lubbers were generally immune from predation. It appears that lubbers have evolved to occupy a relatively predator-free ecological space: they are too large to be attacked by most invertebrate predators and too toxic for most vertebrate predators. We propose an evolutionary scenario whereby a change in feeding behavior toward vertebrate-toxic plants served as an evolutionary breakthrough, setting in motion the subsequent evolution of increased chemical defense and large body size in lubbers. To determine if large size is associated with chemical defense in grasshoppers in general, we compared body sizes of ~ 40 toxic vs ~ 3,000 nontoxic grasshopper species. Our results show that chemically defended species tend to be larger than nondefended grasshoppers, supporting an association between chemical defense and large size in insects. Large size may be favored in insects when vertebrate predation is removed as a strong selective factor.