Prosthesis-related infection is a serious complication for patients after orthopedic joint replacement, which is currently difficult to treat with antibiotic therapy. Consequently, in most cases, removal of the infected prosthesis is the only solution to cure the infection. It is, therefore, important to understand the comprehensive interaction between the microbiological situation and the host immune responses that lead to prosthesis infections. Evidence indicates that prosthesis infections are actually biofilm-correlated infections that are highly resistant to antibiotic treatment and the host immune responses. The authors reviewed the related literature in the context of their clinical experience, and discussed the possible etiology and mechanism leading to the infections, especially problems related to bacterial biofilm, and prophylaxis and treatment of infection, including both microbiological and surgical measures. Recent progress in research into bacterial biofilm and possible future treatment options of prosthesis-related infections are discussed.