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Simple Summary: The pink bollworm, Pectinophora gossypiella, is one of the most damaging pests of cotton worldwide. Cotton has been genetically engineered to produce insect-killing proteins from the bacterium Bacillus thuringiensis (Bt) to control major lepidopteran pests, including the pink bollworm. The Bt proteins in genetically engineered crops are not toxic to people, other vertebrates, or most beneficial insects. Advantages of Bt crops can include pest suppression, improved yields, increased farmer profits, and decreased use of conventional insecticides. In the United States, Bt cotton, sterile moth releases, and other tactics were used to eradicate the pink bollworm. For more than 20 years, Bt cotton has been effective against pink bollworm in China. However, the benefits of Bt crops are reduced when pests evolve resistance, as exemplified by pink bollworm resistance to Bt cotton in India. For each of the two Bt proteins used widely in Bt cotton, the genetic basis of resistance is similar between resistance selected in the lab versus the field, regardless of the country of origin. The results suggest that lab selection can be useful for identifying genes likely to be important in field-evolved resistance to Bt crops and that differences in management practices among countries caused different outcomes. Transgenic crops producing insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) control some important insect pests. However, evolution of resistance by pests reduces the efficacy of Bt crops. Here we review resistance to Bt cotton in the pink bollworm, Pectinophora gossypiella, one of the world's most damaging pests of cotton. Field outcomes with Bt cotton and pink bollworm during the past quarter century differ markedly among the world's top three cotton-producing countries: practical resistance in India, sustained susceptibility in China, and eradication of this invasive lepidopteran pest from the United States achieved with Bt cotton and other tactics. We compared the molecular genetic basis of pink bollworm resistance between lab-selected strains from the U.S. and China and field-selected populations from India for two Bt proteins (Cry1Ac and Cry2Ab) produced in widely adopted Bt cotton. Both lab- and field-selected resistance are associated with mutations affecting the cadherin protein PgCad1 for Cry1Ac and the ATP-binding cassette transporter protein PgABCA2 for Cry2Ab. The results imply lab selection is useful for identifying genes important in field-evolved resistance to Bt crops, but not necessarily the specific mutations in those genes. The results also suggest that differences in management practices, rather than genetic constraints, caused the strikingly different outcomes among countries. [ABSTRACT FROM AUTHOR]