Dental caries, caused by Streptococcus mutans, is a common infection. Caries vaccine has been under investigation for the last 40 years. Many in vitro and in vivo studies and some human clinical trials have determined many pertinent aspects regarding vaccine development. The virulence determinants of Strep. mutans, such as Ag I/II, responsible for adherence to surfaces, glucosyltransferase, responsible for the production of glucan, and the glucan-binding protein, responsible for the attachment of glucan to surfaces, have been known to elicit an antigen-specific immune response. It is also known that more than one antigen or a functional part of the genome responsible for these virulence determinants provide a better host response compared with the monogenic vaccine or complete genome of a specific antigen. To enhance the host response, the use of adjuvants has been studied and the routes of antigen administration have been investigated. In recent years, some promising vaccines such as pGJA-P/VAX, LT derivative/Pi(39-512), KFD2-rPAc and SBR/GBR-CMV-nirB have been developed and tested in animals. New virulence targets need to be explored. Multicentre collaborative studies and human clinical trials are required and some interest from funders and public health experts should be generated to overcome this hurdle.