Non-typeable Haemophilus influenzae (NTHi) is a human-specific mucosal pathogen and one of the most common causes of bacterial infections in children and patients with chronic obstructive pulmonary disease. It is also frequently found in polymicrobial superinfections. Great strides have recently been made in the understanding of the molecular mechanisms underlying NTHi pathogenesis. By using new methodology, such as experimental human colonization models and whole-genome approaches, investigators have shed light upon the various strategies of NTHi that are involved in pathogenesis. These include the escape of the mucociliary elevator, evasion of host immunity, survival in environments with scarce nutrients, and finally participation in polymicrobial infections. Lipooligosaccharide branching, proteinous adhesins, metabolic adaption to nutrient availability and many scavenging systems are implicated in these processes. Interestingly, genome-based studies comparing virulent and commensal strains have identified many hypothetical proteins as virulence determinants, suggesting that much regarding the molecular pathogenesis of NTHi remains to be solved. NTHi is an opportunistic pathogen and highly specialized colonizer of the human respiratory tract that has developed intricate mechanisms to establish growth and survival in the human host. Continued research is needed to further elucidate NTHi host-pathogen and pathogen-pathogen interactions.