Dengue is the most important viral disease transmitted to humans by mosquitoes and is caused by the dengue virus (DENV), which belongs to the Orthoflavivirus genus within the Flaviviridae family. The DENV RNA genome encodes ten proteins: three structural (C, prM, and E) and seven nonstructural (NS1-NS5) proteins. A comprehensive understanding of DENV interactions with both mammalian and mosquito cells is essential for the development of specific antivirals, which are currently lacking. In this chapter, we provide an overview of the viral replicative cycle, with a strong emphasis on the viral RNA genome, the composition of the replicative complexes, and the replication mechanisms. In addition, we discuss DENV-induced remodeling of cellular membranes and cellular responses to infection. Finally, key knowledge gaps and research priorities in the study of virus-cell interactions are highlighted.