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Several species of columnar cacti in the Sonoran Desert contain isoquinoline alkaloids that are toxic to all but the resident drosophilids that feed and breed in necrotic stems. Cytochrome P450 enzymes are known to be involved in the metabolic detoxification of these alkaloids by the desert Drosophila and are consequently responsible for their ability to utilize these substrates. D. melanogaster is not normally exposed to these xenobiotic compounds and cannot live in necrotic cactus tissue. However, a previous study found evidence of a phenobarbital-inducible P450 in adults of this species that is capable of metabolizing cactus alkaloids. The current investigation sought to determine whether D. melanogaster responds to selection for alkaloid resistance. Significant increases in larval viability and adult longevity as well as shorter larvae-to-adult development times were observed after 16 generations of selection on medium containing isoquinoline alkaloids. The selected lines that exhibited a positive response can now be used to assay for changes in gene regulation as a possible mechanism of their response. This information will contribute to the understanding of evolution of P450-mediated resistance in insects. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.