The number of orthopedic implants for bone fixation and joint arthroplasty has been steadily increasing over the past few years. However, implant-associated infection (IAI), a major complication in orthopedic surgery, impacts the quality of life and causes a substantial economic burden on patients and societies. While research and study on IAI have received increasing attention in recent years, the failure rate of IAI has still not decreased significantly. This is related to microbial biofilms and their inherent antibiotic resistance, as well as the various mechanisms by which bacteria evade host immunity, resulting in difficulties in diagnosing and treating IAIs. Hence, a better understanding of the complex interactions between biofilms, implants, and host immunity is necessary to develop new strategies for preventing and controlling these infections. This review first discusses the challenges in diagnosing and treating IAI, followed by an extensive review of the direct effects of orthopedic implants, host immune function, pathogenic bacteria, and biofilms. Finally, several promising preventive or therapeutic alternatives are presented, with the hope of mitigating or eliminating the threat of antibiotic resistance and refractory biofilms in IAI.