Dental caries and dental plaque are among the most common diseases worldwide, and are caused by a mixture of microorganisms and food debris. Specific types of acid-producing bacteria, especially Streptococcus mutans, colonize the dental surface and cause damage to the hard tooth structure in the presence of fermentable carbohydrates e.g., sucrose and fructose. This paper reviews the link between S. mutans and caries, as well as different simulation models that are available for studying caries. These models offer a valuable approach to study cariogenicity of different substrates as well as colonization of S. mutans.