Since Richard Feynman first proposed the idea of nanotechnology in 1959, it has developed into a cornerstone of scientific and medical progress. By focusing on materials with sizes between 1 and 100 nm, nanotechnology has the potential to completely transform drug delivery systems and overcome the drawbacks faced by conventional methods. Nanomaterials, with their unique properties, offer enhanced efficiency, bioavailability, and targeted delivery, offering groundbreaking solutions to challenges faced in this field. However, there are toxicological hazards associated with the unparalleled advantages of nanoparticles in drug delivery. Although nanoparticles’ distinct physicochemical characteristics—such as size, form, surface charge, and crystallinity—allow them to pass through physiological barriers, they also give rise to questions regarding their safety. Factors like the accumulation of nanoparticles due to their small size and charged surfaces can lead to adverse effects, emphasizing the need for a nuanced understanding of nanotoxicity. It is essential to evaluate the safety of nanomaterials for the responsible advancement of drug delivery systems. This entails thorough characterization, assessment of interactions with biological systems, identification of exposure pathways, and long-term monitoring of potential adverse effects. This chapter will provide a comprehensive exploration of the toxicology and safety concerns associated with the use of nanomaterials in drug delivery systems, along with emphasizing the critical need for a thorough understanding of potential risks.