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This review identifies trends in the study of interactions between Staphylococcus aureus and humans. When nasal colonization is in the neutral state, infection clearly represents a state of host–pathogen disbalance. The features leading from apparent homeostatic colonization to pathogenesis are identified at an increasing rate.Persistent carriage of S. aureus predisposes to infection but limits bacteraemia-associated mortality. Intermittent carriage is usually imposed and of lesser clinical relevance. The nature and function of several staphylococcal virulence factors have been elucidated and near complete gene catalogues have been established. There does not seem to be a difference in virulence, however, between methicillin-susceptible and resistant S. aureus. Biological selection takes place in the nose and innate immune features relevant to colonization have been discovered. Acquired immunity remains underexposed, but the host factors involved in the host–pathogen interaction have been identified.Virulence assessment of S. aureus has been facilitated by novel technology: genome-wide inventories of virulence potential can be made and new pathogenic mechanisms have been presumptively identified. These involve invasion procedures but also (innate) immune evasion strategies. These cross-fertilizing developments shed light on the feasibility of novel prophylactic or therapeutic strategies for combating staphylococcal carriage and disease.