After its annexation to Cleveland in 1872, the neighborhood new known as Fairfax underwent a period of rapid residential development which continued until about 1920, when the area's population reached 34,000 - approximately 85% of its 1950 peak. During the neighborhood's prime, such streets as Cedar and Quincy were lined with thriving retail businesses, attractive single-family houses and a number of ornate apartment buildings.

Euclid Avenue, near the neighborhood's northern border, became the site of many of Cleveland's largest and most architecturally-distinguished churches. Among the earliest remaining examples is the Euclid Avenue Congregational Church at East 96th Street, a Gothic/Romanesque building constructed in 1872.

Fairfax is also home to three nationally-recognized institutions. The foremost of these is the Cleveland Clinic, established in 1921 and now ranking as Cleveland's largest private employer, with a staff of approximately 8,000. Just to the west, at East 86th and Euclid, is the Cleveland Playhouse, an architectural and cultural landmark founded in 1917 and expanded in 1983 to incorporate three state-of-the-art theaters under a single roof. Finally, the Karamu House in an inter-racial theater of arts center which dates from 1917 (and has been located at its present site since 1949).

Although the first of Fairfax's residents were New Englanders and European immigrants, middle-income African-Americans had become the dominant group as early as 1930. By 1970, 96% of the neighborhood's residents were African-American. Between 1950 and 1980, an exodus of many middle-income households reduced the population of Fairfax from its peak of over 39,000 to less than 13,000. Household incomes and housing values in 1990 had fallen to less than half of the citywide average.

Continuing expansion of the Cleveland Clinic and recent completion of the Church Square shopping center (along the neighborhood's northern border) are factors which are now strengthening the market for private development in Fairfax.