Respiratory infections remain common and may be more difficult to treat because new microbes have been identified; commensal flora can become pathogens; and antibiotic resistance is developing, especially to Streptococcus pneumoniae. Contributing to the severity of pneumonia is the increasing number of more susceptible hosts—immunodeficient patients, created as a by-product of modern medical therapy or from infection with HIV, and elderly patients who have associated illnesses. Better strategies to replete immunocompromised hosts are required. Vaccination to modify infection with S. pneumoniae must be given higher priority by health care providers. New means to immunize the respiratory mucosal surface are needed. Research approaches to consider involve 1) targeting (carrying) relevant antigens to appropriate antigen-processing cells in the airways, eg, dendritic cells; and 2) coupling the immunomodulatory effects of cytokines, eg, interleukin-12. Interleukin-12, for example, can stimulate mucosal antibody responses producing S-IgA and IgG and cause T lymphocytes to produce interferon-γ that can enhance microbial killing by macrophages.