Cytochrome P450 monooxygenases (P450) are membrane-bound hemoproteins that play important roles in conferring protection against both naturally occurring phytochemicals and synthetic organic insecticides. Despite the potential for common modes of detoxification, cross-resistance between phytochemicals and synthetic organic insecticides has rarely been documented. In this study, we examined the responses of a susceptible strain of corn earworm, Helicoverpa zea (Boddie), a polyphagous noctuid, to exposure by an allelochemical infrequently encountered in its host plants and by an insecticide widely used for control purposes. Within a single generation, survivors of xanthotoxin exposure displayed higher levels of tolerance to α-cypermethrin than did unexposed control larvae. The F₁ offspring of xanthotoxin-exposed survivors also displayed higher α-cypermethrin tolerance than did offspring of unexposed control larvae, suggesting that increased α-cypermethrin tolerance after xanthotoxin exposure represents, at least in part, heritable resistance. Administration of piperonyl butoxide, a P450 synergist, demonstrated that resistance to both xanthotoxin and α-cypermethrin is P450-mediated. α-Cypermethrin-exposed survivors, however, failed to show superior growth on xanthotoxin diets. Assays with control larvae, larvae induced by both xanthotoxin and α-cypermethrin, and survivors of LD₅₀ doses of both compounds indicated that H. zea midgut P450s are capable of metabolizing both xanthotoxin and α-cypermethrin. Metabolism of each compound is significantly inhibited by the presence of the other compound, suggesting that at least one form of P450 in H. zea midguts degrades both compounds and may constitute the biochemical basis for possible cross-resistance. Compared with control larvae, xanthotoxin- and α-cypermethrin-induced larvae displayed 2- to 4-fold higher P450-mediated metabolism of both compounds. However, xanthotoxin- and α-cypermethrin-exposed survivors exhibited much higher (2.5- to 11-fold) metabolism of both compounds than did the induced larvae. The metabolism results, like the bioassay results, are consistent with the interpretation that increased α-cypermethrin tolerance after xanthotoxin exposure is attributable mainly to heritable resistance.