With the incidence of dengue fever increasing all over the world, there is an urgent need for therapies. While drug discovery for any disease is a long and difficult process with uncertain success, dengue fever poses an additional complication in that most of the target patient population is young and lives in developing countries with very limited health care budgets. Recent progress in drug discovery for dengue and an analysis of approaches toward hepatitis C virus (HCV) therapeutics suggest that NS5 polymerase is the most promising target for dengue. Moreover such inhibitors may be useful for several other flaviviral diseases. NS3 proteases will be more challenging targets, especially if oral delivery is desired. Recent work has shown that potent inhibitors can be designed readily, but optimization of pharmacokinetic parameters will probably be a long an arduous task, especially since the primary binding pockets prefer to bind basic amino acids. NS3 helicase can also be considered a viable drug target for flaviviral diseases. It has however proved to be a challenging for HCV and selectivity issues versus human helicases must be overcome.