Historically, the highest incidence rates of invasive Haemophilus influenzae disease in the world were found in North American and Australian Indigenous children. Although immunization against H. influenzae type b (Hib) led to a marked decrease in invasive Hib disease in countries where it was implemented, this disease has not been eliminated and its rates in Indigenous communities remain higher than in the general North American population. In this literature review, we examined the epidemiology of invasive H. influenzae disease in the pre-Hib vaccine era, effect of carriage on disease epidemiology, immune response to H. influenzae infection and Hib vaccination in Indigenous and Caucasian children, and the changing epidemiology after Hib conjugate vaccine has been in use for more than two decades in North America. We also explored reasons behind the continued high rates of invasive H. influenzae disease in Indigenous populations in North America. H. influenzae type a (Hia) has emerged as a significant cause of severe disease in North American Indigenous communities. More research is needed to define the genotypic diversity of Hia and the disease burden that it causes in order to determine if a Hia vaccine is required to protect the vulnerable populations.