Cumulative risk refers to the combined threats from exposure via all relevant routes to multiple stressors including biological, chemical, physical, and psychosocial entities. Cumulative risk assessment is a tool for organizing and analyzing information to examine, characterize, and possibly quantify the combined adverse effects on human health or ecologic resources from multiple environmental stressors. The U.S. Environmental Protection Agency (EPA) has initiated a long-term effort to develop future guidelines for cumulative risk assessment, including publication in 2003 of a framework that describes important features of the process and discusses theoretical issues, technical matters, and key definitions. The framework divides the process of cumulative risk assessment into three interrelated phases: a) planning, scoping, and problem formulation; b) analysis; and c) interpretation and risk characterization. It also discusses the additional complexities introduced by attempts to analyze cumulative risks from multiple stressors and describes some of the theoretical approaches that can be used. The development of guidelines for cumulative risk assessment is an essential element in the transition of the U.S. EPA risk assessment methodology from a narrow focus on a single stressor, end point, source, pathway, and exposure route to a broader, more holistic approach involving analysis of combined effects of cumulative exposure to multiple stressors via all relevant sources, pathways, and routes.