Orthopedic infection is refractory to cure. Staphylococcus aureus (S. aureus) is the main causative pathogen responsible for orthopedic infection. S. aureus is capable of not only colonizing bone matrix, but also invading osteoblasts, which may play a significant role in the persistence and recurrence of osteomyelitis. Internalization requires the involvement of cytoskeletal elements, including actin microfilaments, microtubules and clathrin-coated pits. Microfilaments are most significant in the invasion process. S. aureus is capable of remaining alive in osteoblasts for a long period of time. Decreased sensitivity to antibiotics capable of penetrating host cells increases the difficulties of eradicating S. aureus. Osteoblasts, invaded by S. aureus, play a significant role in the initiation and maintenance of inflammatory immune responses. These osteoblasts recruit leukocytes and phagocytes to the site of inflammation via the expression of cytokines. Apoptosis is observed in osteoblasts invaded by S. aureus. Recruitment of osteoclasts and other immunocytes plays a crucial role in the resorption and destruction of bone.