Chronic osteomyelitis is associated with angular or rotational deformity, deformities of the neighboring joints, limb length discrepancy, a deep cavity in the bone and a large sequestrum or dead removal of which creates a large gap. Cierny and Mader have developed a classification system wherein anatomical situation of the chronic osteomyelitis and physiological response of the host are taken into consideration. The first step in the treatment is the identification of the organisms. The antibiotics started according to the sensitivity of the organisms. This chapter aims to present a brief discussion on aggressive treatment of chronic osteomyelitis and covers radical resections, glycocalyx biofilm, antibiotic impregnated beads, treatment of cavity, circumferential gap and bone transport, bone graft, use of calcium sulfate in chronic osteomyelitis, and nutrition status in detail.