The traditional and current use of the latex of Calotropis procera and C. gigantea, two soft-wooded, xerophytic shrubs of the family Apocynaceae, are reviewed against the background of the plants’ chemical constituents and their biological activities. Due to their distinctive latex components, Calotropis plants have been considered a major resource in traditional medicine in many regions. The presence of high amounts of bioactive compounds, which include tannins, flavonoids, triterpenoids, and steroids in the latex of the Calotropis plants, has long been recognized. Peptides and proteins such as peroxidases, peptidases, protease inhibitors, osmotins, lysozymes, and chitinases are all well-studied enzymes associated with the defense system of Calotropis plants against herbivores and diseases. The chemistry and biological activities of the Calotropis plants are thought to be linked to external factors, including the geographic location and the developmental stage of the plant, the season of harvest as well as the storage of the harvested plant, which can lead to a considerable variation in the chemical constituents found.