- Bent's Old Fort National Historic Site - Near La Junta. A restored adobe fur trading post from the 1840s. Learn about the authentic Old West history of traders, trappers and Native Americans, all of whom came to the fort to barter.
- 1 Comanche National Grasslands
- Jackson Lake State Wildlife Area
- Pawnee National Grassland
- Pony Express National Historic Trail Through the Eastern Plains. Even though it was in operation for only 18 months in the early 1860s, and was shut down with the advent of the transcontinental telegraph, the Pony Express has become an indelible part of Wild West lore.
- Rocky Mountain Arsenal National Wildlife Refuge
- Royal Gorge - Canyon City runs a theme park on the rim of this 1,250 ft (380 m) deep canyon, including the Royal Gorge Bridge, highest suspension bridge in the world. (Not for acrophobes).
- Sand Creek Massacre National Historic Site - Near Chivington. Another dark chapter in U.S. relations with Native Americans. In 1864, soldiers from the U.S. military attacked a peaceful encampment of Cheyenne and Arapaho along Sand Creek, on the Eastern Plains. Out of a group of largely women, children and the elderly, 150 were killed.
- Santa Fe National Historic Trail Through the Eastern Plains. Commercial route between Missouri and Santa Fe, New Mexico. The U.S. Army marched along this trail to invade Mexico during the Mexican-American War, the U.S. conquering and annexing California, Nevada, and Utah, as well as parts of Colorado, Arizona, New Mexico, and Wyoming in the process.
Roughly speaking, this region is bounded on the:
- South, by Oklahoma and New Mexico state lines.
- West, by the Front Range, metropolitan Denver Area and South Central Colorado.
- North, by the Wyoming and Nebraska state lines.
- East, by the Kansas state line.
Region boundaries in Colorado are indistinct, and sometimes contentious. If you're looking for a destination/attraction that you think should be in this region, but can't find it, check the pages for Denver Area, South Central Colorado and Front Range.
This is the largest, but most sparsely populated, of Colorado's regions. It occupies the easternmost third of the state, stretching from Nebraska in the north to New Mexico in the south. The only substantial city in the region is Pueblo, on Interstate 25 south of Denver (which is in its own region) and Colorado Springs (treated with the south central region).
Most visitors to Colorado view this area as something one simply drives through quickly, en route to Denver and the mountains. However, there are some points of cultural/historic interest connected with the Santa Fe Trail, which passed through the southern part of the region. The National Grasslands throughout the region preserve wild lands that provide a reminder of what the Great Plains were like before the arrival of settlers from the east.
For more information, see Wikivoyage's article Rail travel in the United States.
During the winter, heavy ice and snow are a major concern, which can make driving difficult and slow going. Always check the weather and road conditions  before heading out. Even on a clear winter's day, make sure your vehicle's wiper fluid reservoir is full. The Colorado Department of Transportation (CDOT)  spreads both sand and magnesium chloride on the roads, which makes for an impenetrable, gluey mess on your windshield.