African swine fever (ASF), an acute, viral hemorrhagic disease in domestic swine with mortality rates approaching 100%, is arguably the most significant emerging disease threat for the swine industry worldwide. Devastating ASF outbreaks and continuing epidemic in the Caucasus region and Russia (2007-to date) highlight significance of this disease threat. There is no vaccine for ASF, thus leaving animal slaughter the only effective disease control option. It is clear, however, that vaccination is possible since protection against reinfection with the homologous strain of African swine fever virus (ASFV) has been clearly demonstrated. Vaccine development has been hindered by large gaps in knowledge concerning ASFV infection and immunity, the extent of ASFV strain variation in nature and the identification of viral proteins (protective antigens) responsible for inducing protective immune responses in the pig. This review focuses on the challenges surrounding ASF vaccine design and development, with an emphasis on existing knowledge gaps.