The respiratory immune response consists of multiple tiers of cellular responses that are engaged in a sequential manner in order to control infections. The stepwise engagement of effector functions with progressively increasing host fitness costs limits tissue damage. In addition, specific mechanisms are in place to promote disease tolerance in response to respiratory infections. Environmental factors, obesity and the ageing process can alter the efficiency and regulation of this tiered response, increasing pathology and mortality as a result. In this Review, we describe the cell types that coordinate pathogen clearance and tissue repair through the serial secretion of cytokines, and discuss how the environment and comorbidity influence this response.