Despite the central role of cardenolides in the classic milkweed-monarch predator chemically-mediated multiple trophic level interaction, very few studies have actually demonstrated that cardenolides protect host plants against herbivores. We tested the hypothesis that cardenolides are an effective chemical defense against generalist insect herbivores by feeding fifth instar gypsy moth, Lymantria dispar (L.) (Lepidoptera: Lymantriidae), larvae artificial diets containing low and high levels of digitoxin, a cardenolide found in leaves of purple foxglove, Digitalis purpurea L. (Scrophulariaceae). Relative to performance of larvae fed the control diet, consumption rate, conversion efficiency, and growth rate were all reduced by at least 60% for larvae fed the relatively low level of digitoxin found in young leaves, and by at least 90% for larvae fed the higher level found in older leaves. Digitoxin acted primarily as a feeding deterrent at the lower level, but was toxic at the higher level. These results suggest that the cardenolide digitoxin is a highly effective plant defense against generalist herbivores.