Although patients with “severe” asthma tend to be characterized by ongoing symptoms and airway inflammation despite treatment with high doses of inhaled and systemic corticosteroids, there is increasing recognition of marked phenotypic heterogeneity within affected patients. Although “precision medicine” approaches for patients with severe asthma are needed, there are many hurdles that must be overcome in daily practice. The National Heart, Lung and Blood Institute's Severe Asthma Research Program (SARP) has been at the forefront of phenotype discovery in severe asthma for the past decade. SARP, along with other international groups, has described clinical severe asthma phenotypes in both adults and children that can be evaluated in the clinical setting. Although these clinical phenotypes provide a good “starting point” for addressing disease heterogeneity in severe asthma in everyday practice, more efforts are needed to understand how these phenotypes relate to underlying disease mechanisms and pharmacological treatment responses. This review highlights the clinical asthma phenotypes identified to date, their associations with underlying endotypes and potential biomarkers, and remaining knowledge gaps that must be addressed before precision medicine can become a reality for patients with severe asthma.