All implanted biomaterials are targets of the host's immune system. While the host inflammatory response was once considered a detrimental force to be blunted or avoided, in recent years, it has become a powerful force to be leveraged to augment biomaterial-tissue integration and tissue repair. In this review, we will discuss the major immune cells that mediate the inflammatory response to biomaterials, with a focus on how biomaterials can be designed to modulate immune cell behavior to promote biomaterial-tissue integration. In particular, the intentional activation of monocytes and macrophages with controlled timing, and modulation of their interactions with other cell types involved in wound healing, have emerged as key strategies to improve biomaterial efficacy. To this end, careful design of biomaterial structure and controlled release of immunomodulators can be employed to manipulate macrophage phenotype for the maximization of the wound healing response with enhanced tissue integration and repair, as opposed to a typical foreign body response characterized by fibrous encapsulation and implant isolation. We discuss current challenges in the clinical translation of immunomodulatory biomaterials, such as limitations in the use of in vitro studies and animal models to model the human immune response. Finally, we describe future directions and opportunities for understanding and controlling the biomaterial-immune system interface, including the application of new imaging tools, new animal models, the discovery of new cellular targets, and novel techniques for in situ immune cell reprogramming.