Summary: Members of the Alphavirus genus are classified into New World and Old World groups based upon their disease characteristics and primary areas of endemicity. The two groups exhibit noteworthy differences in pathogenesis during human infection, with Old World viruses primarily causing febrile and arthritogenic diseases and the New World viruses causing encephalitis. In this review, we summarize the major factors contributing to disease manifestations observed in murine models of alphavirus infection. We concentrate upon differences between particular viruses as they relate to interaction with myeloid lineage cells (particularly dendritic cells and macrophages), both in terms of virus replication efficiency and host cell responses to infection. In addition, we discuss the effects of mutations acquired during cell culture‐adaptation of alphaviruses upon our understanding of important factors in pathogenesis. Finally, we focus on the role of host innate immune responses, in particular the type I interferon (IFN‐α/β) system, in determining the permissivity of myeloid and other cell types. Recent contributions to the current understanding of identities and mechanisms of action of IFN‐α/β‐induced antiviral effectors in vitro and in vivo are also discussed.