This review focuses on recent clinical and translational discoveries in severe and uncontrolled asthma that now enable phenotyping and personalized therapies in these patients. Although asthma is common in both children and adults and typically responds to standard therapies, a subset of individuals with asthma experience severe and/or persistent symptoms despite appropriate therapies. Airflow obstruction leading to frequent symptoms requiring higher levels of controller therapy is the cardinal feature of severe asthma, but the underlying molecular mechanisms, or endotypes, are diverse and variable between individuals. Two major risk factors that contribute to severe asthma are genetics and environmental exposures that modulate immune responses, and although these often interact in complex manners that are not fully understood, certain endotypes converge in severe asthma. A number of studies have evaluated various features of patients with severe asthma and classified patients into phenotypes with clinical relevance. This phenotyping is now incorporated into clinical practice and can be used to guide advanced biological therapies that target specific molecules and inflammatory pathways that contribute to asthma pathogenesis.