Respiratory tract infections associated with nontypeable Haemophilus influenzae (NTHi) are a major cause of morbidity and mortality in both developed and nonindustrialized nations. The success of this organism as a colonizer and pathogen is due to its lack of reliance on any single mechanism of attachment and its ability to respond rapidly to host defense mechanisms by antigenic variation of proteins and enzymes. First we review the interaction between NTHi and the human host, with particular emphasis on mechanisms of adhesion, increased mucin production, and evasion of host defenses via immunoglobulin A (IgA) proteases, epithelial cell entry, and antigenic variation. Then we review vaccine strategies with emphasis on the potential of outer membrane components of NTHi to stimulate appropriate humoral and cellular immune mechanisms for prevention of infection or immunomodulation of chronically infected individuals.