Dengue is the most common viral disease in the tropical and subtropical regions of the world. At present no vaccine or antiviral drugs are available to treat a dengue infection, which leaves supportive care in hospitals as the only available treatment option. Since dengue epidemics often put great strain on healthcare systems, there is an urgent need for novel strategies to combat this disease. The development of vaccines for dengue is complicated by the presence of four different serotypes, which has increased the importance of antiviral drug discovery. In the past 10 years, dengue has changed from a disease that was basically unknown to drug discovery scientists into a vibrant field of research for both biologists and chemists. In this chapter, we will review the different drug targets that have been identified for dengue and critically assess the progress that has been made in antiviral drug discovery. While these efforts have not yet resulted in a clinical development candidate, the progress has been impressive, considering the limited resources. Nevertheless, a concerted effort is required to identify drug candidates for the most promising targets, dengue NS3 protease and dengue NS5 polymerase.