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Owing to its convenient location at the confluence of the Tanana and Yukon Rivers in Interior Alaska, Tanana was once a traditional trading post and seasonal settlement for Koyukon Athabaskan Indians.

In 1880, a commercial trading post, Harper's Station, opened nearby, and more development followed. In 1898, Fort Gibbon was founded to maintain the telegraph line between Fairbanks and Nome. A post office was established, and several other trading posts developed around the turn of the century.

Today, Tanana is still largely an Athabaskan community. Its 2011 population, according to Alaska Department of Labor estimates, was 231. Residents retain many cultural traditions including potlatches, dances, foot races and subsistence lifestyles. Subsistence foods include salmon, whitefish, moose, bear, ptarmigan, waterfowl, and berries.

The Missionary Oblates of Mary Immaculate brought the first Catholic presence to Tanana. In 1862, Oblate Fr. Jean Seguin arrived and stayed at Tanana for a year. Oblate Bishop Isidore Clut visited 10 years later. Then, in 1878, came Bishop Charles Seghers (he would later be appointed an Archbishop, in 1880; and would later be murdered near Nulato, 1886); who would later be called "the founder of the Alaska missions."

In 1887 missionary priests of the Society of Jesus became active in the region. A Jesuit priest for whose patron saint the mission is named, was stationed at Tanana in 1887-88; then again in 1904-06. In 1904 he bought a small house, with a small annex, which served as a small residence, and a small chapel. St. Aloysius was founded.

A number of priests visited St. Aloysius over the years, usually out of Galena, Nulato or Fairbanks. Most were Jesuits, though Diocesan clergy have also served the parish; as has a Xaverian Brother.

Religious Sisters maintained a strong Catholic presence in Tanana for many years. Ursuline Sisters ministered in residence there from 1968 to 96, serving St. Aloysius in various capacities. Sisters of Providence from Fairbanks taught catechism courses at St. Aloysius during the summers of 1963-72.

Presently, parishioner Lois Huntington serves as parish administrator of St. Aloysius; a Franciscan Brother serves as pastoral minister, visiting from his home base in Galena. Celebrations of the Word with Holy Communion replace Sunday Mass when a priest is unavailable.