Chronic osteomyelitis in adults is managed with prolonged courses of intravenous antibiotics in conjunction with surgical debridement of necrotic bone. Over the past 40 years, there has been no paradigm shift in this approach, as randomized controlled trials of this standard of care compared to alternatives such as prolonged oral antibiotics are scarce. However, there have been many small trials, case reports, and review papers evaluating the effectiveness of oral treatment for chronic osteomyelitis. The oral route for infections requiring prolonged treatment is intuitively and practically more favorable due to several advantages, the most important of which is the avoidance of long-term IV antimicrobial therapy with its complications, inconvenience, and cost. In this paper, we review the literature evaluating oral antibiotic therapy in the management of chronic bone infections since 1975. The majority of osteomyelitis infections are caused by , hence we focus on its treatment using oral antibiotics; however, we also emphasize subpopulations of patients with diabetes, implanted hardware, and with less common bacterial organisms. The primary objective of this review is to promulgate clinical recommendations on the use of oral antibiotics in bone infections in the context of initial therapy, transition from intravenous therapy, and the role of chronic suppression. The secondary objective is to summarize current knowledge of the specific oral antimicrobial agents that are commonly utilized, together with a synopsis of the available literature pertaining to their pharmacokinetic/pharmacodynamic properties and duration of therapy in bone infection.