Ecuador's Yasuní Man and the Biosphere Reserve—located at the intersection of the Amazon, the Andes mountains, and the equator—is home to extraordinary biodiversity and a recently contacted Amazonian indigenous group known as the Waorani (or Huaorani). Relatives of the Waorani, the Tagaeri and Taromenane, still live in voluntary isolation deep in the reserve, with no peaceful contact with the outside world. The Yasuní Biosphere Reserve also sits atop large reserves of crude oil, Ecuador's chief export, and contains an abundance of valuable timber species. This volatile combination has led to intense conflicts, and subsequently, increased international interest and concern. To make the issues confronting Yasuní more accessible to a growing audience of interested parties, we synthesized information on the biological, social, and political issues of the region, providing a concise overview of its modern history and conservation challenges. We constructed a chronology of key events in the Yasuní region over the past century and a series of maps designed to guide readers to a better understanding of the area's complicated array of overlapping designations. Main topics of analysis and discussion include: the Waorani and their ancestors living in voluntary isolation, Yasuní National Park, illegal logging, missionary impacts, oil-development-related impacts and conflicts, and the Ecuadorian government's innovative Yasuní-ITT Initiative (ITT: Ishpingo–Tiputini–Tambococha).