Transgenic crops producing Becillus thuringiensis (Bt) Berliner (Bacillales: Bacillaceae) toxins target key insect pests in cotton, Gossypium hirsutum L., and maize, Zea mays L., cropping systems. The pink bollworm, Pectinophora gossypiella (Saunders) (Lepidoptera: Gelechiidae), is currently the target of an area-wide eradication program with the purpose to eliminate pink bollworm from cotton-producing areas of the U.S. and adjacent areas of northern Mexico. Transgenic Bt cotton is a key component of the program. Evolution of resistance to Bt cotton could jeopardize the eradication program and diminish success of long-term control of pink bollworm populations. Molecular monitoring for known resistance alleles and bioassays indicated that pink bollworm resistance to Bt cotton in the U.S. remains rare. However, recent discovery of field-evolved resistance to Bt cotton in India emphasizes the need for diligent resistance monitoring and stewardship of the Bt transgenic technology. Resistance to Cry1Ac in laboratory-selected strains of pink bollworm may involve at least two resistance mechanisms, based on characterization of cadherin-based resistant strains and a newly selected Bt4R strain. In all previous resistant strains of pink bollworm, resistance involved mutations in a cadherin gene encoding for a functional Cry1Ac toxin receptor. Selection of the Bt4R strain using Bt cotton bolls and Cry1Ac in diet revealed a novel mechanism of resistance that differs from previously described Cadherin mutations.