Early diagnosis of osteomyelitis continues to be a clinical problem. Multiple imaging modalities are being used for the diagnosis of osteomyelitis, but none of them is ideal for all cases. The choice of modality depends on several factors based on an understanding of the pathophysiologic aspects of different forms of osteomyelitis. After a brief introduction outlining some basic principles regarding the diagnosis of osteomyelitis, pathophysiologic aspects are reviewed. Advantages and disadvantages of each imaging modality and their applications in different forms of osteomyelitis are discussed. The use of different imaging modalities in the diagnosis of special forms of osteomyelitis, including chronic, diabetic foot, and vertebral osteomyelitis, and osteomyelitis associated with orthopedic appliances and sickle cell disease is reviewed. Taking into account the site of suspected osteomyelitis and the presence or absence of underlying pathologic changes and their nature, an algorithm summarizing the use of various imaging modalities in the diagnosis of osteomyelitis is presented.