Ebola viruses (EBOV) cause severe illnesses in humans with a high rate of mortality that approaches 90%. Novel therapies with potent and selective activity against EBOV are urgently needed for the prevention and treatment of Ebola virus disease (EVD). We propose to execute an innovative high throughput screening campaign using a unique reverse genetics system. This screen is expected to yield new inhibitors targeting EBOV replication that will serve as starting points for medicinal chemistry hit-to-lead efforts. If successful, we will deliver one or more new lead series targeting EBOV infection.