BACKGROUND: Patients with severe refractory asthma have not achieved asthma control, even with high doses of ICS, usually in combination with LABAs and other maintenance treatments. OBJECTIVE: The most promising approaches currently under investigation are those which reduce airway eosinophils in patients with severe refractory asthma and a persisting airway eosinophilia. RESULTS: Monoclonal antibodies against IL-5 have been shown to improve lung function, improve asthma control, reduce exacerbation risk and allow reduction or elimination of maintenance oral corticosteroids in this subset of patients. Bronchial thermoplasty may provide benefit in improving control and reducing exacerbations in selected patients. The addition of the muscarinic antagonist, tiotropium also improves airflow obstruction, but its benefit on exacerbation risk is not yet established. Other developments being evaluated in severe refractory asthma are CXCR2 antagonists in patients with a persisting neutrophilic airway inflammation, and CRTh2 antagonists, both of which are small molecule antagonists, and hMabs against IL4 and IL-13. Finally, other approaches to reduce receptor numbers, using inhaled anti-sense, has shown to reduce allergen-induced airway eosinophilia, and combining different anti-sense against different targets may become a feasible treatment option. CONCLUSIONS: A variety of new treatment options are being investigated to help improve overall asthma control in patients with severe refractory asthma. These include medications to optimize lung function; bronchial thermoplasty to reduce airway smooth muscle in central airways; and those which target specific inflammatory cells or receptors of inflammatory mediators. CLINICAL RELEVANCE: Patients with severe refractory asthma have the greatest unmet treatment needs to improve asthma control and reduce exacerbation risk. New treatment approaches have been identified which will benefit subsets of these patients. Phenotyping patients is necessary to select those likely to benefit.