The total joint replacement is recognized as one of the most effective medical arbitrations leading to increased mobility, pain relief, and an overall restored function of the joint. Unfortunately, prosthetic debris accumulates after long-term wear of the implant leading to activation of the innate immune response and periprosthetic osteolysis. Understanding the intricate biological mechanisms underlying the innate immune response to implant debris would support the development of novel pharmacological treatments to prolong the life span of the implant. This article provides a detailed description on the role of the innate immune system in response to implant debris, emphasizing the most recent research and outstanding questions. Furthermore, a critical discussion is presented on the novel pharmacological treatments currently under investigation to prevent implant failure.