Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a heterogeneous upper airway disease that is prevalent globally. Recent research into the molecular basis of the disease has led to the development of biologics as a new therapeutic option for severe and recalcitrant forms of CRSwNP. Mepolizumab is a monoclonal antibody targeting IL-5, one of the signature cytokines of the type 2 immune response and which plays an important role in the pathogenesis of CRSwNP. Here we present the latest evidence behind mepolizumab, examining disease pathophysiology and pharmacology, as well as data from clinical trials, real-life studies and meta-analyses. As we welcome this promising step forward into precision medicine, we discuss practical issues and future perspectives on mepolizumab and biologics for CRSwNP.