Orthohantaviruses are rodent-borne, negative-sense RNA viruses that are capable of causing severe vascular disease in humans. Over the course of viral evolution, these viruses have tailored their replication cycles in such a way as to avoid and/or antagonize host innate immune responses. In the rodent reservoir, this results in life long asymptomatic infections. However, in hosts other than its co-evolved reservoir, the mechanisms for subduing the innate immune response may be less efficient or absent, potentially leading to disease and/or viral clearance. In the case of human orthohantavirus infection, the interaction of the innate immune response with viral replication is thought to give rise to severe vascular disease. The orthohantavirus field has made significant advancements in understanding how these viruses replicate and interact with host innate immune responses since their identification by Dr. Ho Wang Lee and colleagues in 1976. Therefore, the purpose of this review, as part of this special issue dedicated to Dr. Lee, was to summarize the current knowledge of orthohantavirus replication, how viral replication activates innate immunity, and how the host antiviral response, in turn, impacts viral replication.