La Crosse virus (LACV) is an arthropod-borne RNA virus with substantial potential for future spread in North America. La Crosse virus is responsible for La Crosse encephalitis, a leading cause of arboviral encephalitis in children in the United States. Primarily transmitted by Aedes triseriatus (Eastern treehole) mosquitos and amplified by small mammal hosts, LACV has caused infections throughout the upper Midwest and, more recently, the mid-Atlantic and southeastern United States. Notably, in recent years, infections have also been identified increasingly in the Appalachian region. Anthropogenic and environmental factors have likely contributed to recent LACV spread, including the introduction of invasive vector species (especially Ae. albopictus), biotic interactions between and among vector and host species, land-use change, habitat disturbance, increased human travel and transport, and rising global temperatures. Prevention and control strategies, such as increased surveillance of vector and host populations, increased awareness among populations at risk for infection, and increased awareness among physicians are needed to limit future spread. Continued climate change with increases in global temperatures and erratic weather patterns may result in the expansion of competent mosquito vector species and thus could facilitate the geographic spread of LACV.