Alaska Commercial Company was established 13 miles downriver from Tanana in 1880. In 1881, the Church of England from Canada built a mission 8 miles down river.  Between 1887 and 1900, an elaborate school and hospital complex, the St. James Mission, was constructed. It became an important source of services and social change along Yukon and Tanana rivers.  The St. James Hospital was transferred to the BIA administration in the 1920s.  In 1898, Fort Gibbon was founded at Tanana to maintain the telegraph line between Fairbanks and Nome. A post office was also established, and several other trading posts developed around the turn of the century. Ft. Gibbon was abandoned in 1923.  During World War II, an air base was established near Tanana as a refueling stop for the lend-lease aircraft program.

New hospital facilities were built in 1949; and during the 1950s, hospital administration was transferred to the U.S. Public Health Service.  The hospital complex was a major economic factor during this period.  The hospital employed 54 persons with a payroll of $1.6 million, but was closed in 1982.  The hospital facilities were remodeled for use as a health clinic, counseling center, tribal office, and Regional Elders Residence.

The Alaska Department of Commerce, Community and Economic Development in 2006 certified the population for Tanana as 261.  Alaska Natives comprise 81.5% of the population.  2000 U.S. Census records show 166 housing units for the village.  The Census specified that 100 residents were unemployed. The median household income in 2000 was $29,750 or per capita income was $12,077. Residents living below the poverty level was 22.95 percent.

Two-thirds of the full-time jobs in Tanana are with the city, school district or native organizations.  BLM firefighting, trapping, construction work and commercial fishing are important seasonal cash sources.  Residents depend on subsistence fishing (17 commercial fishing permits) and harvesting of whitefish, moose, bear, ptarmigan, waterfowl and berries.