Polymicrobial interactions on mucosal surfaces can influence inflammation, immunity, and disease outcome. Here, we review how host responses to colonization in the upper respiratory tract with the bacterial pathogen Streptococcus pneumoniae can be altered by co-infection. Recent advances provide a mechanistic understanding of how mucosal immunity can be subverted at distinct immunological time-points during pneumococcal colonization by other pathogens such as Haemophilus influenzae, influenza type A and Staphylococcus aureus. These examples use animal models of co-infection to highlight how otherwise effective host responses can be rendered ineffective by co-infection, and vice versa. The complex microbial ecology of mucosal sites must be considered to fully understand how immune responses in a natural setting influence the outcome of host-pathogen interactions.