- Small mammals constitute the largest consumer of the creosote bush. Jackrabbits are the only known mammal to eat the plant's leaves, which have a bitter taste and are only eaten when jackrabbits can find no other source of food. Desert woodrats as well as kangaroo rats depend on creosote seeds as a staple of their diet, also utilizing the bush's root system for shelter. Other small mammals also use the bush for shelter but do not really depend on the creosote as a food source.
- There is an entire desert ecosystem developed around the creosote bush in the insect world. More than 60 species of insects have evolved specifically around the bush. One example of this is a walking stick that mimics the creosote from birth to death, looking like new creosote leaves when young and resembling exactly the old twig growth of a creosote once mature. A type of scale insect, Tachardiella larreae, consumes the creosote bush and excretes lac, a substance some people use for sealing things, or as glue. Within this insect-based ecosystem, many of the insects feed off of the creosote bush and many feed off each other.
- There are 22 species of bees that are adapted to and feed specifically and only on the creosote bush. The creosote bush depends on them for pollination just as much as they depend on the bush for a nectar source.
- Many lizards and reptiles depend on the creosote for a shelter source, but for the most part they do not consume the bush. The chuckwalla is an exception. This lizard, the largest in the American Southwest, eats the leaves and flowers of the creosote.
- The creosote is said to be the most-used medicinal herb in the North American desert. It is known for its antioxidant properties and is employed by Native Americans and ethnobotanists to cure a number of ailments. A few deaths have been associated with the ingestion of creosote, and the FDA has considered banning the sale of the plant's extract, but to date it is still commercially available.
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