Japanese encephalitis (JE) is the most common zoonotic arboviral encephalitis, caused by the single-stranded RNA virus, the Japanese encephalitis virus (JEV) of the genus Flavivirus (family Flaviviridae). It has rapidly expanded its clutches and spread to a large geographical area including South Asia and Western Pacific Rim up to the Australian Torres Strait Islands. Despite vaccination and preventive measures, Japanese encephalitis continues to have an incidence of 68,000 cases annually with a significant mortality and morbidity in terms of disability-adjusted life years (DALY). Although only 0.1–1% of infected develop encephalitis and majority remain asymptomatic, JE continues to be the disease with the highest global burden, because of its long-term neurological sequelae. JE virus is transmitted naturally through an enzootic cycle to birds and pigs, which serve as the amplifying hosts, and to humans via accidental exposure by bite of the Culex (Culex tritaeniorhynchus and Culex vishnui) mosquitoes. The transmission peaks in rainy seasons in temperate regions and is endemic all year round in tropical regions. JE predominantly affects children <15 years in endemic areas and both children and young adults in non-endemic areas who are rural inhabitants. Before the vaccine era, it was an important cause of exotic encephalitis among travelers, the incidence of which has declined since then. After an incubation period of 5–15 days, it produces a prodrome of fever, coryza, and myalgia, which over the next few days progresses to acute encephalitis with headache, vomiting, and altered sensorium, often heralded by seizures. Important neurological manifestations include generalized tonic-clonic seizures, focal motor seizures, parkinsonian syndrome, cranial nerve palsies, and acute flaccid paralysis. Long-term sequelae include residual paralysis, declined cognitive and language functions, and behavioral abnormalities. Despite enhancement in our knowledge of the pathophysiology of the disease, scientific research lags in terms of exploring new therapeutic avenues to reduce mortality and morbidity associated with the disease. Global eradication of JE is a herculean task, and thus, we need to explore new drugs and repurpose old ones by rapid large-scale pragmatic randomized clinical trials, thereby speeding up the development of treatment of other emerging Flaviviruses.