The pathogenesis of disease caused by H. influenzae type b and non-typeable H. influenzae involves multiple steps. Although similar mechanisms are used to promote colonization of the nasopharynx, both organisms express unique virulence determinants that dictate the spectrum of disease they are able to cause. A major difference is the expression of a PRP capsule by type b strains. This alone is sufficient to facilitate intravascular survival and the onset of invasive disease. Although it is a major determinant of virulence, the capsule has played a useful role as the basis of the highly successful H. influenzae vaccine. In contrast, no such highly conserved virulence determinant is common to non-typeable strains of H. influenzae, which complicates the search for a candidate vaccine for this group of organisms. As a consequence, while disease due to type b stains is now rare, non-typeable strains continue to be a significant cause of morbidity and even mortality in children. New insights into non-typeable H. influenzae virulence factors may give opportunities for vaccine or other strategies to prevent disease.