The burden of musculoskeletal infections is permanently growing. A probable explanation for this development could be the increasing number of elderly people undergoing extensive surgery using implants and prosthetic devices while having more significant comorbidities (e.g. cardiovascular, metabolic and malignant). However, a relative reduction of acute (hematogenous) osteomyelitis compared to the occurrence of much more complex situations, such as diabetic foot syndrome or chronic osteitis and prosthetic implant infections is being observed. This poses new challenges for the clinician in managing these patients. Furthermore, there is the evolving threat of antimicrobial resistance as well as the increasing amount of infections with Gram-negative pathogens. Several aspects have to be considered for successful management of musculoskeletal infections: the site of infection and feasibility of local surgical treatment, the effectiveness of antimicrobial treatment, the inclusion of comorbidities and their specific treatment in an advanced therapeutic concept as well as the interdisciplinary approach led by surgeons and infectious disease specialists.