Asthma is a complex syndrome with multiple phenotypes and endotypes. Asthma exacerbations are not only the clearest indictor of the morbidity of asthma and of the risk for mortality due to asthma, but also comprise a significant amount of the cost to care for poorly controlled asthma. There continues to be significant disparity in the prevalence, mortality, and morbidity due to asthma. Patients with asthma who suffer recurrent exacerbations are considered to have exacerbation-prone asthma (EPA). Efforts to characterize patients with frequent exacerbations show that the etiology is likely multifactorial. Research to determine the intrinsic risk factors for EPA include studies of both genetic and inflammatory biomarkers. External factors contributing to exacerbations have been extensively reviewed and include viral infection, environmental exposures, air pollution, and psychosocial and economic barriers to optimizing health. It is likely that EPA occurs when patients who have an increased underlying intrinsic/biological risk are placed in a given exposome (environments with a variety of exposures and triggers including allergens, pollution, stress, barriers, and occupational exposures). It is the social construct combined with underlying biology that frequently drives an EPA phenotype.