[3] Advocates characterize Sheldon as one of the few intact sagebrush steppe ecosystems in the Great Basin, one that hosts a variety of wildlife endemic to the unique environment.

The dominant plant life consists of drought-tolerant species such as sagebrush, juniper, mountain mahogany, bitterbrush, and aspen.

Desert fishes, greater sage-grouse, migratory birds, mule deer, and the pygmy rabbit are all residents, with the pronghorn – North America's fastest land mammal – being the best known and numbering around 3,500.

[5] The pronghorn played a key role in the refuge's history, as approximately 94 percent of the current protected land area was originally set aside as the Charles Sheldon Antelope Range in 1936.

[7] The refuge contains the very active and popular Virgin Valley Opal Mining District whose mineral rights were grandfathered-in with the establishment of the sanctuary.

Denio 52 WSW is a weather station located within the Sheldon National Wildlife Refuge, near Yellow Peak (Nevada).

[7] Proposals to cull some of the alleged excess population of the mustang in the Sheldon National Wildlife Refuge were drawing public concern as of 2008[update].

[4] In response, the American Wild Horse Preservation Campaign has accused the USFWS of conducting "helicopter round-ups during foaling season" in the Sheldon Refuge.