Since the discovery of filoviruses in 1967, there have been more than 40 outbreaks with high case-fatality rates causing more than 30,000 deaths in humans. Filovirus disease (FVD) involves the dysregulation of many host physiological processes. While many advances in the field have taken place since the first outbreaks, the dearth of small animal models that translate the features observed during FVD in humans has limited our understanding of the pathology. Here, we describe the generation and use of human immune system (HIS) mice as a preclinical model to investigate FVD in a human-like immune environment.