Mycobacterium tuberculosis is a remarkably successful human pathogen owing to its ability to enter into a persistent state. Towards obtaining a better understanding of the mycobacterial persistence mechanisms, several in vitro, ex vivo and animal models, that mimic one or more features of the host milieu, have been developed. Although none of the models is complete in itself, valuable insights into the persistent state have been derived from each one of them. Here, we review the evolution of the various in vitro models for persistent bacterial infection and how the study of dormant bacilli in cell-infection models has provided us with a better understanding of bacterial adaptation and persistence in the face of the challenges posed by the host.