Human integrative physiology related to exercise dates back to the beginning of 1900, and although the degree to which the detailed mechanisms could be explained at that time, those studies were instrumental in asking the fundamental questions in exercise physiology and performance that could then gradually over the years be better and better described and understood. The development of more detailed e.g. genetic, biochemical and molecular technology allowed for more mechanistic studies in in vitro systems and in several animal models. Several of these findings provided basic insight and created hypothesis for human body function in exercise, but were also overly optimistic, and often subsequent integrative physiological studies in humans revealed a lack of confirming the suggested mechanisms to be really crusial for bodily function in “real human life”. The paramount degree of redundancy in human body function makes it often difficult to pinpoint the importance of a single factor for a specific e.g. cardiovascular, metabolic or tissue adaptive function with physical training and in acute exercise performance. This fact does challenge the human integrative physiology research, but also asks for innovative approaches that can be performed in humans. Only when taking basic science back to human integrative studies can it be confirmed that suggested adaptive mechanisms are in fact important for human performance. The lecture will provide examples where integrative human studies have been used to understand human exercise physiology and pathophysiology when high-level exercise leads not only to performance but also to tissue disorders and injuries.