Ensuring reliable access to clean and affordable water is one of the greatest global challenges of this century. As the world's population increases, water pollution becomes more complex and difficult to remove, and global climate change threatens to exacerbate water scarcity in many areas, the magnitude of this challenge is rapidly increasing. Wastewater reuse is becoming a common necessity, even as a source of potable water, but our separate wastewater collection and water supply systems are not designed to accommodate this pressing need. Furthermore, the aging centralized water and wastewater infrastructure in the developed world faces growing demands to produce higher quality water using less energy and with lower treatment costs. In addition, it is impractical to establish such massive systems in developing regions that currently lack water and wastewater infrastructure. These challenges underscore the need for technological innovation to transform the way we treat, distribute, use, and reuse water toward a distributed, differential water treatment and reuse paradigm (i.e., treat water and wastewater locally only to the required level dictated by the intended use). Nanotechnology offers opportunities to develop next-generation water supply systems. This Account reviews promising nanotechnology-enabled water treatment processes and provides a broad view on how they could transform our water supply and wastewater treatment systems. The extraordinary properties of nanomaterials, such as high surface area, photosensitivity, catalytic and antimicrobial activity, electrochemical, optical, and magnetic properties, and tunable pore size and surface chemistry, provide useful features for many applications. These applications include sensors for water quality monitoring, specialty adsorbents, solar disinfection/decontamination, and high performance membranes. More importantly, the modular, multifunctional and high-efficiency processes enabled by nanotechnology provide a promising route both to retrofit aging infrastructure and to develop high performance, low maintenance decentralized treatment systems including point-of-use devices. Broad implementation of nanotechnology in water treatment will require overcoming the relatively high costs of nanomaterials by enabling their reuse and mitigating risks to public and environmental health by minimizing potential exposure to nanoparticles and promoting their safer design. The development of nanotechnology must go hand in hand with environmental health and safety research to alleviate unintended consequences and contribute toward sustainable water management.