Since the launch of the USGS’s Prompt Assessment of Global Earthquakes for Response (PAGER) system in fall of 2007, the time needed for the U.S. Geological Survey (USGS) to determine and comprehend the scope of any major earthquake disaster anywhere in the world has been dramatically reduced to less than 30 min. PAGER alerts consist of estimated shaking hazard from the ShakeMap system, estimates of population exposure at various shaking intensities, and a list of the most severely shaken cities in the epicentral area. These estimates help government, scientific, and relief agencies to guide their responses in the immediate aftermath of a significant earthquake. To account for wide variability and uncertainty associated with inventory, structural vulnerability and casualty data, PAGER employs three different global earthquake fatality/loss computation models. This article describes the development of the models and demonstrates the loss estimation capability for earthquakes that have occurred since 2007. The empirical model relies on country-specific earthquake loss data from past earthquakes and makes use of calibrated casualty rates for future prediction. The semi-empirical and analytical models are engineering-based and rely on complex datasets including building inventories, time-dependent population distributions within different occupancies, the vulnerability of regional building stocks, and casualty rates given structural collapse.