Infection is a feared complication and a common cause of loss of function following open fractures. Despite the evidence supporting the administration of prophylactic antibiotics after open fractures, data demonstrating the optimal regimen is lacking. We reviewed the data supporting the current prophylaxis recommendations and the changing epidemiology of Staphylococcus aureus, the most common cause of surgical site infection in patients with open fractures. Although widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has been described in both hospital and community settings, to date, no studies have addressed the need for prophylaxis against MRSA in patients with open fractures. Until well-designed randomized trials are conducted, we recommend that providers consider selecting antibiotics active against MRSA for open fracture prophylaxis based on the local prevalence of MRSA carriage and individualized risk factors.