<p>Osteomyelitis, defined as inflammation of bone, is a highly morbid disease that is most commonly caused by bacterial infection. Infectious osteomyelitis occurs across a spectrum of ages and affects previously healthy individuals as well as individuals with medical comorbidities. Establishment of osteomyelitis typically occurs following one of three general pathological mechanisms, including haematogenous seeding of healthy or injured bone, extension of a contiguous soft tissue infection, or direct inoculation of microorganisms into the bone following trauma. A wide spectrum of microbial pathogens can cause osteomyelitis in these settings. The most common aetiologies share common pathogenic traits such as the propensity to form biofilms, the elaboration of immunoevasive toxins and virulence factors, and the ability to adhere to and invade bone tissue. Challenges in diagnosing, prognosing and treating osteomyelitis remain owing to limitations of conventional cultures, absence of faithful biomarkers, inability to delineate acute versus chronic infection, and therapeutic recalcitrance. Despite prolonged antimicrobial therapy, many individuals with osteomyelitis fail treatment and go on to develop highly morbid complications. Improvements in the management of osteomyelitis will require an ongoing commitment to multidisciplinary clinical care, basic and translational research to uncover pathophysiological mechanisms of disease, and sustained investments in new approaches for the diagnosis, treatment and mitigation of complications.</p>