In this overview, we summarize the findings of the literature with regards to physiology and pathophysiology of ultra-marathon running. The number of ultra-marathon races and the number of official finishers considerably increased in the last decades especially due to the increased number of female and age-group runners. A typical ultra-marathoner is male, married, well-educated, and ~45 years old. Female ultra-marathoners account for ~20% of the total number of finishers. Ultra-marathoners are older and have a larger weekly training volume, but run more slowly during training compared to marathoners. Previous experience (e.g., number of finishes in ultra-marathon races and personal best marathon time) is the most important predictor variable for a successful ultra-marathon performance followed by specific anthropometric (e.g., low body mass index, BMI, and low body fat) and training (e.g., high volume and running speed during training) characteristics. Women are slower than men, but the sex difference in performance decreased in recent years to ~10-20% depending upon the length of the ultra-marathon. The fastest ultra-marathon race times are generally achieved at the age of 35-45 years or older for both women and men, and the age of peak performance increases with increasing race distance or duration. An ultra-marathon leads to an energy deficit resulting in a reduction of both body fat and skeletal muscle mass. An ultra-marathon in combination with other risk factors, such as extreme weather conditions (either heat or cold) or the country where the race is held, can lead to exercise-associated hyponatremia. An ultra-marathon can also lead to changes in biomarkers indicating a pathological process in specific organs or organ systems such as skeletal muscles, heart, liver, kidney, immune and endocrine system. These changes are usually temporary, depending on intensity and duration of the performance, and usually normalize after the race. In longer ultra-marathons, ~50-60% of the participants experience musculoskeletal problems. The most common injuries in ultra-marathoners involve the lower limb, such as the ankle and the knee. An ultra-marathon can lead to an increase in creatine-kinase to values of 100,000-200,000 U/l depending upon the fitness level of the athlete and the length of the race. Furthermore, an ultra-marathon can lead to changes in the heart as shown by changes in cardiac biomarkers, electro- and echocardiography. Ultra-marathoners often suffer from digestive problems and gastrointestinal bleeding after an ultra-marathon is not uncommon. Liver enzymes can also considerably increase during an ultra-marathon. An ultra-marathon often leads to a temporary reduction in renal function. Ultra-marathoners often suffer from upper respiratory infections after an ultra-marathon. Considering the increased number of participants in ultra-marathons, the findings of the present review would have practical applications for a large number of sports scientists and sports medicine practitioners working in this field.