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Dengue is currently an expanding global health problem. Development of an effective tetravalent dengue vaccine is considered a high public health priority. The uniqueness of the dengue viruses (DENVs) and the spectrum of disease resulting from infection has made dengue vaccine development difficult. This review focuses on the current critical issues in dengue vaccine development.DENVs are arboviral flaviviruses transmitted by Aedes mosquitoes causing a spectrum of clinical disease. DENV infections are a significant global health problem; the WHO estimates that more than 120 countries have endemic DENV transmission resulting in 70–500 million infections, 2.1 million clinically severe cases, and 21 000 deaths annually. There are currently no licensed antivirals or vaccines to treat or prevent dengue. The DENV–host interaction of infection is unique with severe disease a consequence of sequential dengue infection, viral immune evasion, host antibody enhancement, host immune activation, and genetic predisposition. This unique pathogen–host interaction complicates dengue vaccine development and creates provocative questions in vaccine development such as identifying markers of protective immunogenicity, the potential role of antibody in vaccine failures, and the possible impact of large-scale vaccination on the evolution of wild-type DENV.Dengue is a unique and complex disease; developing a dengue vaccine has proven equally complex. In this review, the authors discuss issues that will prove to be critical to the success or failure of the dengue vaccine development effort.