Hemorrhagic fever viruses are associated with rapidly progressing severe disease with high case fatality, making them of public health and biothreat importance. Effective antivirals are not available for most of the members of this diverse group of viruses. A broad spectrum strategy for antiviral development would be very advantageous. Perhaps the most challenging target would be the highly immunosuppressive filoviruses, ebolavirus and marburgvirus, associated with aerosol infectivity and case fatalities in the 80-90% range. Here we report that activation of evolutionarily conserved cytosolic viral nucleic acid sensor, RIG-I can cause severe inhibition of ebolavirus replication. These findings indicate that RIG-I-based therapies may provide an attractive approach for antivirals against Ebola hemorrhagic fever, and possibly other HF viruses.