Structured RNA molecules and helicase enzymes are essential for viral function, especially in the case of Hepatitis C virus (HCV) and flaviviruses (such as Dengue or Yellow Fever), which are major threats to world health. Our goal is to solve the molecular structure of the HCV and flaviviral replicase machines, and to deduce their roles in pathogenicity. In this way, we hope to develop new, broad-spectrum therapeutics against existing and emerging viruses. We recently determined the molecular mechanism of RNA unwinding by the NS3 helicase from HCV using a combination of enzymology and crystallography. Having established this foundation, we have are now developing approaches for visualizing intact replicases and monitoring their dynamical function in living cells.