In 1847, the cathedral was moved from its former location further south to the corner of Eoff and 13th Street, and the church was titled to Saint James the Apostle.

Bishop Donahue conceived a design and began to interview possible architects, eyeing Edward J. Weber of Pittsburgh, a rising star in Church architecture, as a likely candidate.

Bishop Donahue's death in October 1922, before work had even begun may have scuttled all plans, were it not for a serendipitous fire in 1923 that did significant damage to the cathedral structure.

The sculpture in the tympanum of the main doorway, depicting "Christ in Majesty", was carved by Francis Aretz, who also sculpted the Stations of the Cross inside.

Carved symbols of the Four Evangelists occupy quadrants around the wheel window, as in the Toscanella church, and a statue of St. Joseph stands above.

The exterior pulpit and sounding board, both of stone, on the northeast corner of the facade derive from examples such as the cathedral in Prato, near Florence.

The eye-catching mural, “Enthroned Christ and the Communion of the Saints,” which fills the half-dome of the apse, was painted by Felix B. Lieftuchter, and George W. Sotter designed the medieval-style stained glass.

A free-standing ciborium, another feature typical of Lombard Romanesque churches, protects the marble high altar on which the tabernacle rests.

In 1973, changes were made to the interior in keeping with Vatican II standards, and in 1995–1996, the cathedral was restored and cleaned, including the murals and stained glass.

In 1973, Bishop Joseph Hodges, the fifth Bishop of Wheeling (later, Wheeling-Charleston) oversaw renovations made to the liturgical space according to the norms set by the Second Vatican Council: the main altar was brought forward and centered under the dome, the original ambo (pulpit) and communion rail were removed, and side pews were reoriented to face the central altar.

Plans for the reorganization included closing the existing elementary school due to low enrollment and renovating the building into a new chancery.

These included the development of a community central courtyard and a garden dedicated to the Virgin Mary, adding to the sense of place and worship.