Developing new methods for antiviral drug discovery will pave the way for finding compound leads that could target either virus life cycle or cellular elements essential for virus replication. Flaviviruses are arthropod-borne, pathogenic agents that cause severe diseases in animals and humans. Flavivirus infection, co-infections, and serotypes immune interactions raise a significant global public health concern. Flaviviruses include dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV). The global dissemination of flavivirus vectors, like mosquitoes and ticks, lead to the spread of these viruses to non-endemic areas of the world. No effective vaccines or antiviral drugs exist to combat flavivirus infections. Thus, further research to identify crucial viral and host factors for flavivirus replication is essential to develop effective treatments. Flavivirus NS3 and NS5 proteins are multi-functional enzymes that are important for virus replication and are able to be targeted for developing potent inhibitors. Besides, host factors that are crucial for flavivirus replication can be targeted for broad-spectrum antiviral drugs. New methods can be utilized to identify such host factors, like multiplexed digital gene expression profiling using nCounter technology.