Abstract Infection of ruminants with most (but not all) serotypes of bluetongue virus (BTV) leads to a highly blood cell-associated viremia that may be prolonged but not persistent. Furthermore, recovered animals are resistant to reinfection with the homologous virus serotype, which is the basis for vaccination strategies to prevent BTV infection and the clinical disease (bluetongue) that it causes in domestic livestock. BTV infection is initiated at the site of virus inoculation and the associated draining lymph node, from where the virus is then spread in lymph cells to the systemic circulation and secondary sites of replication. Replication of BTV in target cells, notably mononuclear phagocytic cells (dendritic cells and macrophages) and endothelium, leads to the generation of the innate and adaptive immune responses that mediate both initial virus clearance and subsequent resistance to infection with the homologous virus serotype. The goal of this review is to summarize current understanding of these innate and adaptive immune responses of animals to BTV infection.