Most asthma patients are easily managed with a standard combination of therapies consisting of inhaled controller and reliever drugs, but there remains a large unmet need at the severe end of the disease spectrum. For these patients, development of safer and more effective therapies for asthmatic patients with severe refractory disease remains a top priority. Here, drugs in development for the severe asthma sufferers and their specific mechanism-based pharmacological rationale will be reviewed with a focus on biologics. A systematic search of the literature was made using Medline, and publications were selected on the basis of their relevance to the topic. Here, the authors will review the existing efficacy and safety data from clinical trials of some of the new biologic therapies that are in development for severe asthma. Despite strong preclinical data for many of the more recently identified asthma targets, especially those relating to the T-helper 2 allergic pathway, clinical trials with specific biologics have been largely disappointing. However, there is scope for their specific role in distinctively targeted subpopulations of severe asthmatic patients. It is clear that more efforts should be devoted towards establishing new and more efficient key targets. A closer interaction between industry, academia and health workers will be required to achieve this goal effectively.