The human body’s immune system is comprised of various intertwined mechanisms that are constantly acting. We have physical, chemical, and immune barriers that prevent microorganisms from entering the body and actually infecting it. Our bones and joints are, as per definition, septic environments, where no bacteria should be able to get to, as opposed to mucous membranes (nose, airway, and guts) and skin, where there is constant exchange between viruses and bacteria with our natural body environment and its own bacteria, pH, and defense mechanisms. When one of those mechanisms fails, bacteria enters the body, and infection occurs. In this chapter, we will discuss the differences found in bone and joint infections in immunocompromised patients, as opposed to patients with well-regulated immune systems. We will expose the most common causes of bone and articular infection in both primary and secondary immunodeficiencies, their pathogens, and review the most relevant literature on these subjects.