The interactions between biofilms and various oral tissues greatly influence the host’s health. In contrast to extensive investigations on biofilm activities, the complex and dynamic interactions between biofilms and the host are comparatively less studied, mainly due to the difficulties in resembling the in vivo situation of the human oral cavity. Clinical studies, animal models and in vitro models are currently the mostly used approaches to investigate such host-microbe interactions (HMI). Despite that they are complementary to one another, each model has its own strengths and limitations and they cannot be directly compared with each other in order to reach conclusions easily. Understanding to what extent these models mimic the in vivo HMI in the human oral cavity is the first step, and also the basis, for a better interpretation of results from different models.