Regulations governing chemical use often focus on widely used chemicals and acute human health effects of exposure to them as well as their potential to cause cancer and other adverse health effects. But there is increasing interest in approaches and policies to ensure that substances substituted for chemicals of concern are carefully and thoroughly assessed to avoid regrettable substitutions: the replacement of a toxic chemical by another chemical that later proves unsuitable because of persistence, bioaccumulation, toxicity, or other concerns. This report presents a decision framework for evaluating potentially safer substitute chemicals as primarily determined by human health and ecological risks. The framework enables evaluation of the benefits and shortcomings of substitutes and examination of tradeoffs between risks and factors such as product functionality, product efficacy, process safety, and resource use. Case studies illustrate how users in various decision contexts with diverse priorities can apply the framework. The report also highlights how modern information sources such as computational modeling can supplement traditional toxicology data in the assessment process. The report will be an essential resource to the chemical industry, environmentalists, ecologists, and state and local governments.