Performance-enhancing substances are a conflict-ridden topic in the world of medicine, sports, and fitness. The history of performance-enhancing substances dates back to ancient times, when athletes would consume various substances in an effort to enhance their performance, including hallucinogenic mushrooms and herbs. Today, we know that these substances, which, for example, include anabolic steroids, stimulants, beta-blockers, and human growth hormones, can improve physical performance but come with a diversity of potential health risks and ethical concerns. Moreover, besides the pharmacologically classified drugs, many performance-enhancing substances have a natural origin, too. It is essential to distinguish between medically prescribed treatments that are necessary for the health and well-being of individuals and the misuse of performance-enhancing substances for non-medical purposes. Accordingly, the medical use of these substances must be carefully monitored and regulated at all times to ensure that they are used safely and appropriately. On the other hand, the misuse of performance-enhancing substances can induce serious health consequences, including cardiovascular issues, hormonal imbalances, or, for example, psychological effects with dependence and addiction. Finally, the use of performance-enhancing substances presents several ethical challenges, including issues related to fairness, integrity, and the well-being of individuals. The use of performance-enhancing substances remains a controversial and potentially harmful practice in various fields, including sports and fitness. It is essential to underline health, safety, and ethical considerations in all medical decisions related to using performance-enhancing substances. Hence, this book aims to provide current state-of-the-art information and better insight into various challenges related to medical and non-medical use of performance-enhancing substances.