Propolis has been extensively studied and several chemical constituents, mainly flavonoids, terpenes and phenolics, have been identified. With the emerging microbial resistance to antibiotics, the interest in the search for active compounds, mainly secondary metabolites of plants, has been increasing significantly. In this chapter, we describe the characteristics of the main species of native stingless bees found in South America, especially in Brazil, the ancestral use of propolis produced by them, its chemical composition and its potential for the development of new therapeutic compounds. Its chemical composition is very rich, and for many bee species it remains to be unfolded. Its biological properties evaluated so far include the antibacterial, antimycoplasmic, antifungal, antiviral, antioxidant and anti-inflammatory activities, but not for all known bee species. However, their existence is threatened by the introduction of exotic bees in the environment or using pesticides that annually kill millions of individuals. As if that were not enough, we face the destruction of original forests themselves, and the reforestation strategies with exotic plants.