Severe asthma is a heterogeneous disease. Identification of specific sub-phenotypes of asthma may further improve our understanding of its pathophysiology. The genetic and environmental elements that may be important in the development of the disease are poorly understood, but it appears that the pathophysiological background of severe asthma includes both allergic and non-allergic elements. Inflammatory cells are usually present and activated in the airways of patients with severe asthma, and persist despite treatment, but their relevance to lack of asthma control and disease severity is largely unknown. Histopathological studies of severe asthma suggest that 1/2 to 2/3 of patients with severe asthma have persistent large airway tissue eosinophils, despite continued administration of high-dose systemic and inhaled steroids. Severe asthma has also been associated with neutrophilic inflammation, but the precise role of neutrophils is not yet clear. Up to 50% of patients with severe asthma, however, show no evidence of increased airway inflammation. “Steroid resistance” may occur at several levels, not all of which are related to lack of effect of steroids on inflammation. It appears that the factors leading to the development of severe asthma are complex and the disease is probably a mixture of various syndromes that have different elements, but also share similarities at the pathophysiological level. A better understanding of the immunological and histopathological phenotypes of severe asthma should enhance our ability both to understand the pathogenesis of these syndromes and to improve our therapeutic approach, leading to better targeting of both current and novel forms of treatment.