Children with SCD are prone to invasive infections caused by S. pneumoniae and H. influenzae. Osteomyelitis is caused most often by Salmonella species and less often by S. aureus. The chest syndrome and its associated microvascular disease carry a risk of prolonged and severe infections for Mycoplasma, Chlamydia, and probably other lower respiratory pathogens, particularly in the group of children with SCD prone to pain or microvascular sequestration, such as those with SC hemoglobinopathy. Despite three decades of investigation, the immunopathologic mechanisms leading to these increased risks is not completely clear. Bone infarction and microvascular disease probably play a part in the predisposition to osteomyelitis. Dysfunctional IgG and IgM antibody response, a lack of splenic clearance, defects in alternative pathway fixation of complement, and opsonophagocytic dysfunction play a role in the predisposition to invasive infection from polysaccharide-encapsulated organisms. Immunization with the conjugate Haemophilus vaccines has largely controlled infections caused by this pathogen. Early recognition of SCD through neonatal screening allows early and vigorous antibiotic management of febrile episodes in children with SCD and has perhaps provided the greatest benefit. Treatment of acute febrile episodes should include antibiotics active against regional strains of S. pneumoniae and H. influenzae, whereas treatment of febrile lower respiratory infections should include macrolide antibiotics that are active against Chlamydia and Mycoplasma, as well as pneumococci and Haemophilus. To date, no convincing evidence exists for the efficacy of pneumococcal polysaccharide vaccines in children with SCD, but preliminary data with the conjugate pneumococcal vaccines in normal children and those with SCD suggest that they may be as successful as Haemophilus vaccines in controlling this infection once they are available. Prophylaxis with daily penicillin administration is recommended and is well founded on clinical trials. However, problems with pneumococcal penicillin resistance and the association of failure with a lack of compliance to antibiotic regimens will dictate continued reexamination of this modality for the prevention of pneumococcal infections.