Insecticidal toxins derived from the soil bacterium Bacillus thuringiensis (Bt) have been widely used as microbial pesticides to selectively control juveniles of Lepidoptera, Coleoptera, Diptera and soil-dwelling nematodes. Synthetic genes derived from different strains of Bt have been used to produce genetically modified (GM) plants resistant to insects. GM crops represent one of the quickest adopted innovations in agriculture and are nowadays cultivated on about 200 Million ha worldwide. Their use is regulated by specific legislation regionally and an environmental risk assessment prior commercialization is mandatory. While research has produced a relevant body of information, some existing knowledge gaps and the new goals of pest control strategies, pose challenges to scholars, biotech companies and regulators. Effective insecticide resistance management programs, incorporation of GM crops within integrated pest management plans, maintenance of ecological services in agro-ecosystems represent relevant aspects to guarantee that the potential benefits of GM crops are fully achieved.