Surgical flaps are rudimentary tools in reconstructive surgery, especially following extensive solid tumour resections. They cover skin and soft tissue defects but are prone to ischaemia and necrosis. Since their primary aim is reconstruction, they rarely exhibit a therapeutic activity against the treated disease. Attempts have been made to develop a new therapeutic strategy—biologic brachytherapy, which uses genetically engineered surgical flaps as a drug delivery vehicle, allowing the flap tissue to act as a “biologic pump”. This systematic review summarizes the preclinical evidence on using genetically modified surgical flaps. A literature search was conducted in PubMed, EMBASE, Scopus and Web of Science. The initial literature search yielded 714 papers, and, eventually, seventy-seven studies were included in qualitative analysis. The results show that genetic enhancement of flaps has been used as a local or systemic therapy for numerous disease models. Frequently, it has been used to increase flap survival and limit ischaemia or promote flap survival in a non-ischemic context, with some studies focusing on optimizing the technique of such gene therapy. The results show that genetically modified flaps can be successfully used in a variety of contexts, but we need more studies to implement this research into specific clinical scenarios.