The flaviviruses are small single-stranded RNA viruses that are typically transmitted by mosquito or tick vectors. These “arboviruses” are found around the world and account for a significant number of cases of human disease. The flaviviruses cause diseases ranging from mild or sub-clinical infections to lethal hemorrhagic fever or encephalitis. In many cases, survivors of neurologic flavivirus infections suffer long-term debilitating sequelae. Much like the emergence of West Nile virus in the United States in 1999, the recent emergence of Zika virus in the Americas has significantly increased the awareness of mosquito-borne viruses. The diseases caused by several flaviviruses have been recognized for decades, if not centuries. However, there is still a lot that is unknown about the flaviviruses as the recent experience with Zika virus has taught us. The objective of this review is to provide a general overview and some historical perspective on several flaviviruses that cause significant human disease. In addition, available medical countermeasures and significant gaps in our understanding of flavivirus biology are also discussed.