This church was founded on this site as an Episcopal Mission in 1857 and consecrated on Ascension Day in 1858 by James Otey, the 1st Bishop of Tennessee. It was designated as the Diocesan Cathedral in 1871 and since 1983 has been the see of the Diocese of West Tenn. The Chapel was built in 1887 for the Sisters of St. Mary who established St. Mary's School for Girls here in 1873. The Diocesan House was built in 1902. Construction of the present Cathedral began in 1898 and was completed in 1926.
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This church served as a spiritual and relief center during the 1870's Yellow Fever epidemics when 4 sisters, 2 priests and many lay people gave their lives. They are remembered annually as Martyrs of Memphis. During Civil rights conflicts in 1968 ministers of all faiths gathered here before processing to City Hall to seek a peaceful resolution.