Dengue virus is responsible for a significant amount of human disease in predominantly tropical areas of the world. Much effort has focused on the development of vaccines against the four serotypes of dengue, and within the next few years a vaccine is anticipated. Less progress has been made at developing antivirals that might reduce disease severity. Recent advances in the structural biology of dengue virus and other flaviviruses have opened new possibilities for the rational design of small molecule inhibitors of virus replication. This chapter describes the structural attributes of the dengue virion and how knowledge of its structure, assembly, and entry mechanisms are guiding new strategies toward the development of compounds that will interfere with the viral replication process.