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Natural rubber is an essential material, especially for plane and truck tyres but also for medical gloves. Asia ranks first in the production of natural rubber, of which the Hevea tree is currently the sole source. However, it is anticipated that this source alone will not be able to fulfill the growing demand. Guayule, a shrub native to northern Mexico and southern United States, may also contribute. This plant not only contains polyisoprene, but also resin, a mixture of lipids and terpenoids. This review summarizes various aspects of this plant, from the usage history, botanical description, geographical distribution and cultivation practices, down to polyisoprene and resin biosynthesis including their distribution within the plant and molecular composition. Finally, the main processes yielding dry rubber or latex are depicted, as well as the properties of the various extracts along with economic considerations. The aim is to provide a wide picture of current knowledge available about this promising crop, a good feedstock candidate for a multiple-product biorefinery.