The use of animal models and in vitro assays has allowed the identification and functional characterization of an iconic set of Bordetella pertussis factors that contribute to its pathogenesis. Much research on B. pertussis has been focused on the effects of pertussis toxin and adenylate cyclase toxin on pathogenesis and disease progression, and on the function of adherence factors. However, much larger sets of factors have been identified and proposed to be involved in host–pathogen interactions, including B. pertussis manipulating the host’s metabolism to its advantage. The identification of a third player, the resident microbiota, reveals a complex picture that has yet to be investigated. The ongoing studies of the molecular components produced by B. pertussis and their effect on the host during infection, commonly referred to as ‘pathogenesis’ research, are crucial to generate understanding of the host–pathogen interactions necessary to design new approaches to prevent and cure disease.