A normal constituent of the human upper respiratory flora, Streptococcus pneumoniae also produces respiratory tract infections that progress to invasive disease at high rates in specific risk groups. The individual factors that contribute to the development of invasive pneumococcal disease in this distinct minority of persons, include immune (both specific and innate), genetic, and environmental elements. Specific defects in host responses may involve age, deficiencies in levels of antibodies and complement factors, and splenic dysfunction. Combinations of these immune defects contribute to the increased rates of invasive pneumococcal disease in patients with sickle cell disease, nephrotic syndrome, neoplasms, and underlying medical conditions such as diabetes and alcoholic liver disease. The number of risk factors are greatest and the rates of invasive disease are highest in patients with HIV-1 infection, which has emerged as a major risk factor for serious S. pneumoniae infection worldwide.