This plant has a long history of use by humans. It has been used in the southwestern United States as a food, medicine, and dye since prehistoric times and is one of very few wild foods still in use. As food, its seeds can be eaten raw or cooked, or dried and ground into meal for use as a mush. The tender leaves, flowers and shoots can be cooked and eaten as a cooked vegetable or added to cornmeal porridge. Among the Zuni, the leaves gathered in large quantities and hung indoors to dry for winter use. The young leaves are cooked with corn strongly flavored with chili peppers. To reduce its bitter taste, pieces of iron or rust were sometimes added to the cooking pot. Nitrate poisoning can result if too much is consumed. The Tewa and other Southwestern United States tribes often included Cleome serrulata as a 'fourth sister' in the Three Sisters agriculture system because it attracts bees to help pollinate the beans and squash.

In traditional Native American and frontier medicine, an infusion of the plant is used to treat stomach troubles and fevers, and poultices made from it can be used on the eyes. As a dye, the plant can be boiled down until it is reduced to a thick, black syrup; this was used as a binder in pigments for painting black-on-white pottery at least as long ago as 900-1300 by the Ancestral Puebloans. The Navajo still use it to make yellow-green dye for their rugs and blankets. Plant paste is used with black mineral paint to color sticks of plume offerings to anthropic gods, and the whole plant except for the root is used in pottery decorations.

The genus Cleomella has 22 species of native to North America, ranging from southern Mexico through the western and central United States to western and central Canada. The genus The word Cleomella is a combination of the words "cleome" and "-ella", which mean "little cleome". The species name, serrulata, means saw-like, and refers to the minutely toothed sepals. This species is formerly known as Peritoma serrulata and Cleome serrulata.

Found in open fields, roadsides, and other moist disturbed habitats, from 3,000-9,500 ft. throughout western North America.