In 1866, during the reign of Kamehameha V, the Hawaii legislature passed a law that resulted in the designation of Molokaʻi as the site for a leper colony, where patients who were seriously affected by leprosy (also known as Hansen's disease) could be quarantined, to prevent them from infecting others.

In 1893–1894, the Board of Health tried to remove the last fishing village inhabitants in order to expand the colony to encompass the entire Kalaupapa peninsula, including Kalawao.

The opponents to closure pointed out that, although there were no active cases of leprosy in the colony, many of the residents were physically scarred by the disease to an extent that would make their integration into mainstream society difficult if not impossible.

[11] The Kalaupapa Peninsula remains one of the most remote locations in Hawaii due to unique volcanic and geologic activity over millions of years.

Geologists thought that these cliffs were carved by wind and water erosion, but it is now believed that they formed after a third of the northern portion of the island collapsed into the sea.

The offshore islands—'Ōkala, Mōkapu, and Huelo—support this theory, housing original plant species found on Molokai over two thousand years ago such as the rare native loulu palm.

[12] Mōkapu also hosts a remnant population of Emoia impar, the dark-bellied copper-striped skink, which was introduced to Hawaii more recently.

The extremely hot and fast flowing pāhoehoe lava created a flat triangle of land which eventually cooled and connected to the main part of the island.

The National Park Service describes the hike as extremely strenuous due to the steep, uneven surfaces and varied trail conditions.

Kenneth Seamon, the Kalaupapa administrator of the State Department of Health, said that supply deliveries shouldn't be affected since they go by barge and plane.