Prevention and treatment of respiratory infections remain an important health care challenge as the US population ages, contains more susceptible or high-risk people, and encounters new pathogens or antibiotic resistant bacteria. Reasonably protective vaccines against very common microbes are available for childhood and adult immunization, but, generally, these are underutilized. A broader definition of higher risk individuals is evolving, which will include more for immunization. Different approaches to vaccine development through design of new component vaccines are necessary. This review has updated host defense mechanisms at three levels in the human respiratory tract: naso-oropharynx (upper airways), conducting airways, and alveolar space. Examples of representative pathogenic microbes have been inserted at the respective airway segment where they may colonize or create infection (influenza, measles virus, Porphyromonas gingivalis causing periodontitis, Bordetella pertussis, Chlamydia pneumoniae, Streptococcus pneumoniae, and Bacillus anthracis ). Hopefully, microbe-host interactions will suggest new approaches for preventing these kinds of infections.