Multiple studies have been conducted, many within the last 3-5 years, to develop a deeper understanding into how certain chemical substances enhance and improve certain aspects of our performance, both mental and physical. The successful synthesis, isolation and purification of such human performance enhancing substances have led to breakthroughs not only in the treatment of debilitating diseases such as Alzheimer’s and Parkinson’s disease, but also have a significant impact on endurance training. While the chief use of such performance enhancing agents is in the treatment of diseases like anaemia, depression, attention deficit and neurodegenerative disorders, such substances are also misused and sometimes abused in sport. This review highlights 6 major substances used as performance enhancers, namely, creatine, racetams, melatonin, caffeine, cholinergics and EPO. The six substances enhance different features of human performance. The chemistry of these substances, their chemical biology, methods of synthesis and latest data obtained from various clinical trials are discussed.