The Eastern equine encephalitis virus (EEEV) complex comprises mosquito-borne neurotropic alphaviruses maintained in nature by mosquitoes. Although rare, human infections caused by these viruses can lead to febrile illness that may progress to severe encephalitis, for which there are no vaccines for prevention and no specific therapeutics for treatment. Moreover, a high percentage of human cases show long-term neurological sequelae. Here, we review the literature on cases, diagnosis, and management. Current gaps in clinical care include an urgent need to develop rapid diagnostic tests, new therapeutics, and vaccines.