Ginseng occupies a prominent position in the list of best-selling natural products in the world. Compared to the long history of use and widespread research on Asian ginseng, the study of American ginseng is relatively limited. In the past decade, some promising advances have been achieved in understanding the chemistry, pharmacology and structure-function relationship of American ginseng. To date, there is no systematic review of American ginseng. In this review, the different structures of the ginsenosides in American ginseng are described, including naturally occurring compounds and those resulting from steaming or biotransformation. Preclinical and clinical studies published in the past decade are also discussed. Highlighted are the chemical and pharmacological diversity and potential structural-activity relationship of ginsenosides. The goal is that this article is a useful reference to chemists and biologists researching American ginseng, and will open the door to agents in drug discovery.