Objective To provide a comprehensive state-of-the-art review of the emerging role of urine leukotriene E4 (uLTE4) as a biomarker in the diagnosis of chronic rhinosinusitis (CRS), aspirin-exacerbated respiratory disease (AERD), and asthma. Data Sources Ovid MEDLINE(R), Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. Review Methods A state-of-the-art review was performed investigating the role of uLTE4 as a diagnostic biomarker, predictor of disease severity, and potential marker of selected therapeutic efficacy. Conclusions uLTE4 has been shown to be a reliable and clinically relevant biomarker for CRS, AERD, and asthma. uLTE4 is helpful in ongoing efforts to better endotype patients with CRS and to predict disease severity. Implications for Practice Aside from being a diagnostic biomarker, uLTE4 is also able to differentiate aspirin-tolerant patients from patients with AERD and has been associated with objective disease severity in patients with CRS with nasal polyposis. uLTE4 levels have also been shown to predict response to medical therapy, particularly leukotriene-modifying agents.