Complex microbiota are being reported increasingly across a range of chronic infections, including those of the cystic fibrosis airways. Such diversity fits poorly into classical models of sterile tissue infections, which generally involve one species, and where microbe-outcome associations usually imply causality. It has been suggested that microbiota at sites of infection could represent pathogenic entities, analogous to individual species. We argue that our ability to identify causality in microbiota-disease associations is, however, inherently confounded. Although particular microbiota may be associated with clinical outcomes, niche characteristics at sites of infection will shape microbiota composition through exerting selective pressures. Here, we suggest that ecological theory can inform clinical understanding.