Red blood cells (RBCs), also called erythrocytes, are the most abundant type of blood cells. Recently, RBCs have been extensively studied as drug delivery systems because of their remarkable properties, including their inherent biocompatibility, low immunogenicity, flexibility, and long systemic circulation. Over the years, a number of different RBC-based drug delivery systems, including genetically engineered RBCs, nongenetically engineered RBCs, and RBC membrane-coated nanoparticles, have been explored, aiming at diverse biomedical applications. These techniques may address many challenging issues faced by traditional drug delivery systems, as demonstrated by the many successful preclinical results. Novel techniques dedicated to producing drug-carrying RBCs are currently undergoing the transition from preclinical research to the clinical realm. In this Topical Review, we will summarize the latest progress in the development of RBC-based smart delivery systems for various biomedical applications.