The order Didelphimorphia contains the common opossums of the western hemisphere. Opossums probably diverged from the basic South American marsupials in the late Cretaceous or early Paleocene. A sister group is the Paucituberculata, or shrew opossums. They are commonly also called "possums", though that term is more correctly applied to Australian fauna of the suborder Phalangeriformes.

Didelphimorphs are small to medium-sized marsupials, about the size of a large house cat. They tend to be semi-arboreal omnivores, although there are many exceptions. Most members of this taxon have long snouts, a narrow braincase, and a prominent sagittal crest. The dental formula (one side of one jaw) includes 5 incisors (four on the lower jaw), 1 canine, 3 premolars and 4 tricuspid molars. By mammal standards, this is a very full jaw. The incisors are very small, the canines large. Didelphimorphs have a plantigrade stance (feet flat on the ground) and the hind feet have an opposable digit with no claw. Like some primates, opossums have prehensile tails. The stomach is simple, with a small cecum. Opossum reproductive systems are extremely basic, with a reduced marsupium. This means that the young are born at a very early stage. The species are moderately sexually dimorphic with males usually being somewhat larger than females.

Didelphimorphs are opportunistic omnivores with a very broad range of diet. Their unspecialized biology, flexible diet and reproductive strategy make them successful colonizers and survivors in unsettled times. Originally native to the eastern United States, opossums were intentionally introduced into the west during the Great Depression, probably as a source of food. Their range has been expanding steadily northwards, thanks in part to more plentiful, man-made sources of fresh water, increased shelter from urban encroachment, and milder winters. Their range has extended into Ontario, Canada, and they have been found as far north as Toronto.
Opossums are usually nomadic, staying in one area as long as food and water are easily available. Though they will temporarily occupy abandoned burrows, they do not dig or put much effort into building their own. They favor dark, secure areas, below ground or above.

When threatened or harmed, they will "play possum", mimicking the appearance and smell of a sick or dead animal. The lips are drawn back, teeth are bared, saliva foams around the mouth, and a foul-smelling fluid is secreted from the anal glands. The physiological response is involuntary, rather than a conscious act. Their stiff, curled form can be prodded, turned over, and even carried away. Many injured opossums have been killed by well-meaning people who find a catatonic animal and assume the worst. If you find an injured or apparently dead opossum, the best thing to do is leave it in a quiet place with a clear exit path. In minutes or hours, the animal will regain consciousness and escape quietly on its own. Adult opossums do not hang from trees by their tails, though babies may dangle temporarily. Their prehensile tails are not strong enough to support a mature adult's weight, though they often serve as a brace and a fifth limb when climbing. There are also confirmed accounts of the tail being used as a grip to carry bunches of leaves or bedding materials to the nest. Opossums have a remarkably robust immune system, and show partial or total immunity to the venom of rattlesnakes, cottonmouths, and other pit vipers.[citation needed] Thanks to their lower blood temperature, rabies is almost unknown in opossums.