Mepolizumab (Nucala®) is a fully humanized monoclonal antibody against interleukin-5 (IL-5) that is being developed by GlaxoSmithKline. Subcutaneous mepolizumab is approved in the USA for the add-on maintenance treatment of patients aged ≥12 years with severe asthma and an eosinophilic phenotype, and is awaiting approval in the EU. Mepolizumab blocks IL-5 and reduces blood and sputum eosinophil counts in patients with asthma. In the phase III MENSA trial in patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high-dose inhaled glucocorticoid therapy, mepolizumab significantly reduced the annualized exacerbation rate. In the phase III SIRIUS trial, mepolizumab had an oral glucocorticoid-sparing effect in patients with severe eosinophilic asthma requiring systemic glucocorticoid maintenance therapy. This article summarizes the milestones in the development of mepolizumab leading to this first approval for severe asthma with an eosinophilic phenotype.