In 2012, the National Science Foundation (NSF) created a new cross-directorate initiative—Sustainable Chemistry, Engineering, and Materials (SusChEM)—within its Science, Engineering and Education for Sustainability (SEES) portfolio. SusChEM aims to support the discovery of new science and engineering that will provide humanity with a safe, stable, and sustainable supply of chemicals and materials sufficient to meet future global demand. While NSF has historically supported research in this area, the SusChEM effort elevates this interest to a priority. In particular, NSF will support the discovery of new science and engineering that will (1) improve the harvesting and processing of natural resources, (2) develop replacement and substitute chemicals and materials for those that are scarce, toxic, and/or expensive, (3) extend the lifetime of materials through improved durability, (4) reduce energy consumption through improved catalysis, and (5) discover low-energy means of recycling, repurposing, recovering, and reusing chemicals and materials. This article provides an overview of the sustainability challenges that the mathematical, physical, and geological science and engineering communities are well poised to address and presents the National Science Foundation’s vision of the SusChEM initiative.