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Nontypeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae (pneumococcus) are pathobionts that share common environmental niches within the upper respiratory tract. They can form part of the resident upper airway microbiota, but under certain environmental circumstances become pathogenic and induce disease. In children, both organisms have a considerable impact on the healthcare system, commonly causing acute otitis media and pneumonia. They are also associated with chronic biofilm-mediated respiratory infections, such as persistent middle ear effusions and chronic suppurative otitis media, and in the lower airways with protracted bacterial bronchitis and bronchiectasis. Consequently, both organisms are responsible for large numbers of antibiotic prescriptions and substantial healthcare costs. The complex relationship between NTHi and pneumococcal co-interaction during colonization, infection and biofilm formation is poorly understood and a greater understanding is needed to facilitate development of future therapies, and novel interventions and prevention strategies. Co-infections with both bacteria can result in more severe disease, with disease severity likely mediated by their ability to cooperate in some in vivo niches. However, this relationship is not always straightforward, as under certain conditions, these two bacteria compete rather than cooperate. Current opinion supports developing a vaccine targeting NTHi strains, as well as a combined vaccine targeting both NTHi and pneumococci to decrease the respiratory disease burden in young children. This review summarizes our current knowledge of the interactions between NTHi and pneumococci and speculates on the future directions of research to understand how these bacteria co-exist and how to better prevent and treat NTHi and pneumococcal infection., (© 2024 Wiley Periodicals LLC.)