Genetically mediated cell surface engineering is widely explored for modifying both eukaryotic and prokaryotic membranes. These approaches show promise in utilizing engineered membrane-based platforms, such as living cells, membrane-coated nanoparticles, and membrane-derived vesicles, for various biomedical applications. Genetic engineering aims to modify cell membranes with recombinant molecules to enhance biological interactions, improve targeting efficiency, boost immunological responses, and reduce the toxicity of membrane-based therapeutic platforms. Additionally, it can enable the loading of recombinant nucleic acids into the vesicle lumen and facilitate the fusion of recombinant molecules with vesicle surface proteins. This approach enhances drug loading, membrane surface functionalization, and significantly improves the bioactivity, targeting efficiency, and pharmaceutical function of engineered membrane-derived vesicles. This chapter explores advanced gene delivery systems, including viral vectors (e.g., retroviral, adenoviral, lentiviral) and non-viral vectors (e.g., liposomes, polymers, nanoparticles). It discusses genetic engineering strategies for improved drug loading, membrane surface modification, and reduced toxicity of membrane-based platforms. Furthermore, this chapter discusses the application of genetically modified cell membrane platforms for diverse biomedical applications, including cancer therapy, therapeutic production, gene delivery, and targeted disease treatment. This chapter also discusses challenges and future research directions for genetically engineered membrane-based platforms to address unmet clinical needs.