The Chemical Mixture Methodology (CMM) is used for emergency response and safety planning by the US Department of Energy, its contractors and other private and public sector organizations. The CMM estimates potential health impacts on individuals and their ability to take protective actions as a result of exposure to airborne chemical mixtures. It is based on the concentration of each chemical in the mixture at a designated receptor location, the protective action criteria (PAC) providing chemical-specific exposure limit values and the health code numbers (HCNs) that identify the target organ groupings that may be impacted by exposure to each chemical in a mixture. The CMM has been significantly improved since its introduction more than 10 years ago. Major enhancements involve the expansion of the number of HCNs from 44 to 60 and inclusion of updated PAC values based on an improved development methodology and updates in the data used to derive the PAC values. Comparisons between the 1999 and 2009 versions of the CMM show potentially substantial changes in the assessment results for selected sets of chemical mixtures. In particular, the toxic mode hazard indices (HIs) and target organ HIs are based on more refined acute HCNs, thereby improving the quality of chemical consequence assessment, emergency planning and emergency response decision-making. Seven hypothetical chemical storage and processing scenarios are used to demonstrate how the CMM is applied in emergency planning and hazard assessment.