Regular physical activity decreases the risk of cardiovascular disease, type II diabetes, obesity, certain cancers, and all-cause mortality. Nevertheless, there is mounting evidence that extreme exercise behaviors may be detrimental to human health. This review collates several decades of literature on the physiology and pathophysiology of ultra-marathon running, with emphasis on the cardiorespiratory implications. Herein, we discuss the prevalence and clinical significance of postrace decreases in lung function and diffusing capacity, respiratory muscle fatigue, pulmonary edema, biomarkers of cardiac injury, left/right ventricular dysfunction, and chronic myocardial remodeling. The aim of this article is to inform risk stratification for ultra-marathon and to edify best practice for personnel overseeing the events (i.e., race directors and medics).