Chemicals improve our lives through use in products and services, and the number of chemicals in use continues to grow. Sometimes a chemical is determined to be hazardous to people or the environment, yet replacing it with another chemical may introduce new hazards. Understanding the risks and tradeoffs associated with chemical substitution could benefit industry, regulators, and consumers. It can take years to fully understand whether a chemical is hazardous to people or the environment. Removing hazardous chemicals quickly from the market can lead to replacement with substitutes whose safety risks are largely unknown. Developing best practices and using approaches such as artificial intelligence and manufacturing less- or non-toxic chemical substitutes using green chemistry could help reduce future chemical substitution risks.