Agricultural biotechnology has been widely adopted in agriculture but is also the focus of controversy. Questions have arisen regarding food and environmental safety. In the US, responsibility for ensuring agricultural and environmental safety is delegated to the USDA and EPA, respectively. The FDA has primary responsibility for food safety, with the exception that the EPA has responsibility for the safety of proteins in plants associated with insect defense mechanisms. The food safety assessment, whether performed by the FDA or the EPA, requires evaluation of the safety of 1) the newly added DNA, 2) the safety of the newly introduced gene product and 3) the overall safety of the balance of the food. A paradigm called 'Substantial Equivalence' guides the assessment. The principal food safety issues for new varieties crops are 1) potential toxicity of the newly introduced protein(s), 2) potential changes in allergenicity, 3) changes in nutrient composition, 4) unintended effects giving rise to allergenicity or toxicity and 5) the safety of antibiotic resistance marker-encoded proteins included with the transgene. All of these must be taken in the context of the predicted range of dietary exposures. The evaluation seeks to establish that there is a 'reasonable likelihood of safety' and that new varieties are as safe as or safer than crops produced by traditional methods. Indeed, after extensive safety testing and some five years of experience with such crops in the marketplace, there is not a single report that would lead an expert food scientist to question the safety of such transgenic crops now in use.