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Despite its 1989 designation as a threatened species, the desert tortoise has declined in numbers by ninety percent since the 1980s. Although federal protection made it illegal to harm desert tortoises or remove them from the southwestern North American deserts, this measure has been insufficient to reverse the species' decline. The lack of recovery is partly due to the desert tortoise's low reproductive potential. Females breed only after reaching fifteen to twenty years of age, and even then may only lay eggs when adequate forage is available. The average mature female produces only a few eggs annually. From these precious eggs, hatchlings emerge wearing soft shells that will take five years to harden into protective armor. The vulnerable young are entirely neglected by adult tortoises, and only five percent ultimately reach adulthood.

Predators are blamed for a majority of tortoise deaths; ravens alone are estimated to cause more than half of the juvenile tortoise deaths in the Mojave Desert. Tortoise eggs and juveniles can also fall prey to mammals and other reptiles. For protection from predators, as well as from desert temperature extremes, tortoises of all ages burrow into the earth. However, if rabbits and rodents are scarce, larger predators may exhume tortoises from their burrows, devouring even mature tortoises despite their hardened shells. Further, tortoises are susceptible to a wide range of pathogens. The population decline is partly due to upper respiratory tract disease (URTD), characterized by nasal and ocular discharge and palpebral edema. In 2006, more than 80 percent of captive desert tortoises had anti-mycoplasma antibodies, seropositive indication of the disease. Released captive tortoises can rapidly spread URTD into the wild population with devastating consequences.

Though desert tortoises are well adapted to arid habitats, and adults can survive a year without access to water, they rely heavily on moisture in the vegetation consumed in spring, when they surface from their hibernal dormancy. The loss of native plants to grazing livestock and invasive plant species, then, may lessen the tortoise's resistance to pathogens, though the tortoises do also dig precipitation basins in the soil and linger near one when rain is impending.