Paper devices have recently attracted considerable attention as a class of cost-effective cell culture substrates for various biomedical applications. The paper biomaterial can be used to partially mimic the in vivo cell microenvironments mainly due to its natural three-dimensional characteristic. The paper-based devices provide precise control over their structures as well as cell distributions, allowing recapitulation of certain interactions between the cells and the extracellular matrix. These features have shown great potential for the development of normal and diseased human tissue models. In this review, we discuss the fabrication of paper-based devices for in vitro tissue modeling, as well as the applications of these devices toward drug screening and personalized medicine. It is believed that paper as a biomaterial will play an essential role in the field of tissue model engineering due to its unique performances, such as good biocompatibility, eco-friendliness, cost-effectiveness, and amenability to various biodesign and manufacturing needs.