The increasing number of prosthesis implantations and higher life expectancy lead to a growing number of periprosthetic infections (PPI). Optimal therapy necessitates interdisciplinary coordination of surgical and antimicrobial treatment. Challenges in the treatment are the increased occurrence of resistant pathogens, selection of adequate antimicrobial and surgical treatment strategies, inappropriate pretreatment and comorbidities of patients. Current treatment concepts lead to a high success rate in terms of infection eradication, when correctly applied. The individual expectations and underlying conditions of each patient must be considered when determining the therapy concept. The first step is to distinguish between acute and chronic infections. In acute infections the prosthesis can be retained but chronic infections necessitate a complete exchange of the prosthesis. Complicating factors, such as compromising soft tissue and bone conditions, osteomyelitis and infections caused by difficult-to-treat bacteria should, however, always be treated by a complete exchange of the prosthesis, even for acute infections. The antimicrobial treatment must be tailored to the causative agent, the surgical strategy as well as comorbidities and drug intolerances of the patient. It is important to distinguish between biofilm-active eradication therapy with rifampicin for gram-positive pathogens and quinolones for gram-negative organisms and suppression therapy. This article gives a structured presentation of the therapy algorithm.