After losing his bid for a third presidential term in 1912, Theodore Roosevelt became lonely in depressed. In the past, he dealt with such situations by throwing himself into physical difficult or dangerous scenarios. After his first wife died, he went to the badlands for two years where he worked as a ranch hand and cowboy. An opportunity would soon arrive to visit South America for a speaking tour. Seeing this as an opportunity to cleanse himself of his recent defeat, Roosevelt agreed to go. He was also interested in going because, as a naturalist all his life, he knew that there were many scientific discoveries to be made in the Amazon.

Roosevelt contacted Father Zahm, a good friend who had been asking Roosevelt to go on such a trip for years. Father Zahm then sought out Anthony Fiala, a man who had nearly died trying to discover the North Pole, to arrange the supplies needed for the trip. George Cherrie would join the trip as the naturalist, with the aim to collect as many specimen of birds and other animals as possible. In addition to these men, the group would meet up with Kermit, Roosevelt's second son, and a large group of Brazilians. One, Rondon, would be the official leader of the expedition.

The group arrived in Brazil on October 18, 1913 and for the next two months Roosevelt went on a political speaking tour of several South American countries. During this time, the expedition transformed from a trip down a known river, to a trip to map out a river that Rondon had discovered several years ago, but never traversed, known as the River of Doubt.

The trip to the River of Doubt began on December 12, 1913. The group took a steam boat up a river as far as they could, at which point they had to travel across the Mato Grasso (highlands) to reach the headwaters at the River of Doubt. The journey to the headwaters was difficult, and it became apparent that the group would not all be able to descend the river. In the end, Roosevelt was forced to cut Zahm, Fiala, and another naturalist who had joined the group. It would just be Roosevelt, Cherrie, Kermit, Rondon, and his contingency of camaradas who would be responsible for the bulk of the work.

The group descended the river in a collection of dugouts (crudely made Brazilian canoes), and met with trouble from the beginning. The dugouts were not able to successfully navigate rapids, forcing frequent and difficult portages through the rain forest. Throughout the journey, they would lose four dugouts and have to build two new ones. All the members became ill, with either malaria or dysentery. One camarada died when trying to navigate a dugout through some rapids (an event that Kermit insisted upon, and almost killed him as well).

In addition to illness, towards the end of the journey they were all on the verge of starvation. One camarada murdered another, and was ultimately left in the jungle to fend for himself. The group encountered evidence of native Indians, but were never attacked. This was, Millard points out, the great miracle of the trip that allowed them to survive.

Of all the members, Roosevelt became the most ill after receiving a large cut on his leg. The wound became infected and, coupled with malaria, ended up almost killing Roosevelt on the journey. At one point he asked Cherrie and Kermit to leave him, but Kermit refused to see his father die. Through sheer force of will, he returned his father home safely.

After returning home safely, there was some skepticism over if Roosevelt and his group had really discovered a previously unknown 1000 mile long tributary of the Amazon. He was soon able to convince his skeptics. The Brazilian government named the river Rio Roosevelt in his honor.

Roosevelt never truly recovered from his illness on the trip, however, and would die just five years later at the age of sixty. Kermit married Belle, his fiancée during the trip, but could never adjust to the non-adventurous lifestyle. He committed suicide in his fifties in Alaska. Rondon lived to ninety-two, and was a Brazilian hero and the eventual Indian rights movement in Brazil.