Flaviviruses and coronaviruses are two large families of medically relevant viruses. They are responsible for COVID-19 pandemic (severe acute respiratory syndrome coronavirus 2), dengue hemorrhagic fever (dengue virus), microcephaly (Zika virus), polio-like paralysis (West Nile virus), viral hepatitis (hepatitis C virus), and countless other diseases. While different in their pathogenic features, these viruses share two key features. First, the virus particles are surrounded by a lipid bilayer which makes them susceptible to inactivation by various detergents including alcohol. In addition, these viruses contain a single-stranded, positive-sense RNA genome. Hence, the replication cycle of flaviviruses and coronaviruses takes place entirely in the cytoplasm of the infected cells. This review will highlight the similarities and differences in the replication cycles of flaviviruses and coronaviruses. The highlight will focus on virus genome translation, replication, and particle assembly. During infection, the viral RNA genome can trigger innate immune responses including types I, II, and III interferons. This review will summarize how flaviviruses and coronaviruses antagonize the interferon response to facilitate virus replication. Finally, the question of how the inflammatory response to flavivirus or coronavirus infection can lead to severe illness will be addressed.