Eastern equine encephalitis virus (EEEV) and Western equine encephalitis virus (WEEV) are enveloped, positive-sense, single-stranded RNA viruses in the Alphavirus family. Both arboviruses are maintained in avian reservoir species and transmitted to mammals, including horses and humans, via mosquito vectors. EEEV is endemic in the Western Hemisphere and causes frequent cases of severe neurologic disease in equine and human patients; cases are expected to increase as climate change and vector dynamics favor geographic spread of the virus. WEEV is detected less frequently and has not been implicated in human or equine disease in the United States since the late 1990s but has recently reemerged in South America causing significant numbers of clinical cases. Both viruses are zoonotic diseases of public health concern, and diagnosis can be complicated. While effective commercially available vaccines are readily available for horses, no licensed therapeutics or vaccines are available for use in other species.