This article explores the history of exotic drugs through a central but often ignored issue : the use of substitutes. For this purpose, it compares plants originating from the “East” with plants originating from America, because they occupy an opposite spot in this process. On the one hand, the most commonly used oriental remedies in the 16th century have been known since the Middle Ages or even Antiquity. Alongside spices, with which they are often confused, they are among the most highly valued products on the european market. Their cost, and their frequent unavailability, encourage fraud, as well as the search for products that can replace them. On the other hand, American remedies, by definition unknown to the Ancients, are often approached on the basis of their similarity to european, mediterranean and asian pharmacopoeias. They thus enter the european market as substitutes. By observing how physicians and apothecaries used and studied these products during the 16th century, the article draws three main conclusions. First of all, it shows that the humanist rereading of the Ancients accentuated, particularly with regard to the oriental pharmacopoeia, the distinction between “true” or “original” plants and “common” or “vulgar” plants. He then points out that the use of substitutes has been surrounded by mistrust because he could take things that were not equivalent, thus perpetuating confusion and fraud. Finally, it shows that the practice of substitution has also been at the origin of innovations : by attributing, thanks to the interplay of similarities, new uses to plants, some authors have been able to revalue the american pharmacopoeia, which has become more than a reservoir of substitutes.