BACKGROUND During the last decade, polyurethanes and polyureas have emerged as promising alternatives to classical polyacrylate-, polyester- and polyaminoacid-based drug delivery nanosystems. They are not only biocompatible and biodegradable, but also facilitate the manufacture of polymeric nanostructured nanoparticles in quantitative yields. The versatile chemistry reduces the amount of organic solvents used and allows the straightforward multifunctionalization of polymer precursors with the desired targeting molecule at each stage of the process. OBJECTIVE To highlight the common issues encountered in current drug delivery systems (DDSs) and the state of the art of polyurethane and polyurea polymers that self-assemble in a stratified manner by hydrophobic interactions. Finally, we discuss the importance of taking a holistic view when applying polymer nanotechnologies, in order to enhance their efficiency during preclinical and clinical studies. CONCLUSIONS Polyurethane-polyurea nanoparticles (PUUa NPs) emerge as suitable platforms to be manufactured in a cost-effective manner at industrial scale and following environmentally friendly synthetic methods. Furthermore, they allow the controlled delivery of a wide range of drugs and can be rapidly adapted to many clinical requirements by means of FDA-approved precursors. Additionally, the ease with which PUUa nanoparticles are biodegraded ensures control over temporal aspects of drug delivery compared to other nanosystems. These advantages make PUUa NPs attractive drug delivery vehicles as long as adequate safety and ethical guidelines for new NP formulations are developed.