Diamond discusses the multicenter prospective cohort study by F. Moazed and colleagues which identified a strong association between biochemically defined tobacco exposure in patients with sepsis. This study adds to a growing body of literature highlighting the remarkable heterogeneity of ARDS. Despite a lower level of illness severity and a lower level of biochemically determined systemic inflammation as determined by plasma levels of IL-8 and soluble tumor necrosis factor receptor 1, the authors identified that septic patients with either active or passive tobacco exposure had increased odds of ARDS. This level of syndromic heterogeneity at the level of the patient highlights the need to integrate more precision into the design of clinical trials (a one-size-fits-all approach for ARDS therapeutics will not work). Different phenotypes of ARDS will likely require different therapeutics targeting distinct pathways to be effective.