[4] Its subspecific epithet allapaticola originates from the local Seminole Native American term allapattah, which indicates the tropical, dry, deciduous hammocks of South Florida.

[2] This range shift can be attributed to the increased urbanization of Key Largo which has decimated the forests of tropical hardwood hammocks, thus reducing the availability of food, shelter and habitat for the cotton mouse.

[citation needed] This fragmentation and range limitation makes the Key Largo cotton mouse more vulnerable to fires and hurricanes.

The hardwood hammocks they prefer are highly productive forests with a tall canopy and open understory, consisting of a diverse range of species.

The Key Largo cotton mouse builds small nests or dens by lining leaves inside logs, tree hollows, and rock crevices.

Much of the fruit and berries produced by tropical hardwood hammock habitat species can be food items for the occupant cotton mice.

[6] The Key Largo cotton mouse was recognized by the Fish and Wildlife Service in a notice of review on July 28, 1980 (45 FR 49961).

Trash and pollution boost black rat populations, which can outcompete the Key Largo cotton mouse for resources such as food.

[7] Since the habitats of Key Largo cotton mice are at low elevation and fragmented, the species have difficulty finding safe shelter.

Climate change is expected to increase the number of extreme weather events such as hurricanes, worsening the threat to Key Largo cotton mice.

Rising sea levels due to global climate change are also expected to further fragment Key Largo cotton mouse habitats.

Negotiations between the Fish and Wildlife Service and organizations seeking to accelerate construction on Key Largo via water and electricity expansion resulted in exclusion zones in 1980.

In these zones, water and electricity expansion is prohibited in order to protect the Key Largo cotton mouse and other endangered species.

This is important because once an area has access to water and electricity, residential and commercial construction projects (such as houses, stores, and restaurants) can be started.

[6][3] The US Fish and Wildlife Service has recommended several other conservation strategies in order to downlist the Key Largo cotton mouse from endangered to threatened.

[3] In 2023 the Key Largo cotton mouse was featured on a United States Postal Service Forever stamp as part of the Endangered Species set, based on a photograph from Joel Sartore's Photo Ark.