This paper provides an overview of the U.S. regulatory framework governing genetic biocontrol efforts for invasive fish. Genetic biocontrol refers to the intentional release of genetically modified organisms (GMOs) into the environment to control a target population of a non-native species. The terms “genetically modified” and “genetically engineered” are often used interchangeably, despite the scientific distinctions. A GMO is an organism that has had its genetic material altered or modified by humans through any method, including conventional breeding. Genetic engineering, as defined by the Food and Drug Administration (FDA), is the use of recombinant DNA techniques to introduce new characteristics or traits into an organism. GE organisms are therefore a subset of GMOs. As this paper will discuss, existing laws focus on GE organisms raising significant questions as to whether organisms modified without utilizing rDNA techniques fall within the jurisdiction of any federal agency. Under the 1986 Coordinated Framework for Regulation of Biotechnology, three federal agencies have primary responsibility over biotechnology—the Environmental Protection Agency (EPA), the U.S. Department of Agriculture, and the FDA. Because the EPA has exempted biological control agents from regulation as pesticides and no fish species are currently considered plant pests, the FDA is the agency responsible for approving the use of genetically engineered fish for biocontrol. FDA regulates genetically engineered animals through its New Animal Drug Application (NADA) process. The NADA process presents several challenges to effective and transparent regulation of genetic biocontrol, including the FDA’s focus on drug safety, secrecy provisions potentially limiting disclosure of the results of environmental reviews, and the secondary role of the Fish and Wildlife Service, the federal agency with the most experience with invasive species management. In addition, relying on the NADA process creates a significant regulatory gap as NADA approval is only required for GE organisms. The regulatory framework for GMOs created for genetic biocontrol without rDNA technology is unclear and primary responsibility may fall to the states. Given its extensive experience with hatcheries, invasive fish species control, and environmental reviews, the Fish and Wildlife Service (FWS) is the more appropriate agency to review applications for genetic biocontrol. Efforts should be undertaken now, while genetic biocontrol is still in the theoretical stages, to increase the role of the FWS in the permitting process either through formal regulations or more informal mechanisms such as memorandum of understanding.