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Staphylococcus aureus is the most common pathogen causing bone and joint infections (BJI). In India, prevalence of Methicillin resistant Staphylococcus aureus (MRSA) is increasing at an alarming rate and emerged as an important contributor towards the difficult to treat BJI. Currently available anti-MRSA agents have their own limitations with regards to reduced susceptibility as well as safety and tolerability. Furthermore, biofilms over the prosthesis with invariably multi-drug resistant strains leads to complex treatment processes. This necessitates the need to develop and screen new antibiotics against MRSA that can easily penetrate the deep pockets of infection and take care of the challenges discussed. This review aims to discuss on MRSA infection in bone and joint infection, current antibiotic regimen, its associated limitations, and finally, the need to develop new antibiotic therapy for effective management of patients with BJI.