Historically, bone was thought to be immunologically inactive with the sole function of supporting locomotion and ensuring stromaness functions as a major lymphoid organ. However, a myriad of pathogens (bacteria such as staphylococcus as well as viruses including alphaviruses, HIV or HCV) can invade the bone. These pathogens can cause apoptosis, autophagy and necrosis of osteoblasts and lead to lymphopenia and immune paralysis. There are now several detailed studies on how osteoblasts contribute to innate immune and inflammatory responses; indeed, osteoblasts in concert with resident macrophages can engage an armory of defense mechanisms capable of detecting and controlling pathogen evasion mechanisms. Osteoblasts can express the so-called pattern recognition receptors such as TOLL-like receptors involved in the detection for example of lipids and unique sugars (polysaccharides and polyriboses) expressed by bacteria or viruses (e.g. LPS and RNA respectively). Activated osteoblasts can produce interferon type I, cytokines, chemokines and interferon-stimulated proteins through autocrine and paracrine mechanisms to control for viral replication and to promote phagocytosis or lysis of bacteria for example by defensins. Uncontrolled and sustained innate immune activation of infected osteoblasts will also lead to an imbalance in the production of osteoclastogenic factors such as RANKL and osteoprotegerin involved in bone repair.