In 1910, under the direction and authority of the Bishop, the School was entrusted to the direction of Helen Loomis, who served as Principal of the Upper School until 1949. Mary Paoli directed the Lower School until her death in 1922. Today, her name is kept alive by an award given each year in her memory to an eighth-grade student with the highest scholastic average over two years. Katherine Neely acted as Principal of the Lower School from 1922 until 1949. During this era, St. Mary's was located at 1257 Poplar Avenue, at St. Mary's Cathedral.
Major obstacles confronted the successful operation of an independent school during this era of the School's history: two World Wars and the Great Depression. Loomis and Neely triumphantly tackled the challenges of the times. Commencement in 1949 marked both the retirement of Loomis and the last formal activity of the school on Poplar Avenue. In September of that year, St. Mary's relocated to Grace-St. Luke's Episcopal Church and a smaller school reopened to students in kindergarten through the fourth grade. From 1949 through 1958, St. Mary's enjoyed the leadership of Gilmore Lynn, and, for the period of several years, boys attended St. Mary's.
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In 1953, St. Mary's expanded to the sixth grade and relocated to the Church of the Holy Communion at the corner of Walnut Grove and Perkins. In 1958, St. Mary's was incorporated and the Board of Trustees hired Lawrence Lobaugh as the School's first headmaster. By the fall of 1959, St. Mary's enrollment had nearly doubled to 400, and faculty had increased to 30; in 1961 the first issue of the School's yearbook, Carillon, was published; and in 1962 the School was accredited by the Southern Association of Colleges and Secondary Schools.