American history is linked inextricably with religion. Religion has provided justification for domination and conquest, as well as motivation for philanthropy. For many, America represented the opportunity to worship without oppression. While the collection contains many Bibles, sermons, and tracts, religion is also a thread through all genres.

During the 17th century, Europeans settled the Atlantic coastal regions, notably Puritans in New England, Quakers and German Pietists in Pennsylvania, Catholics in Maryland, and Calvinists in Virginia. During the 18th century, the clergy were the most prolific writers in the colonies. The collection includes many early American imprints such as sermons, treatises, pamphlets, and hymnals by Jonathan Edwards, Cotton and Increase Mather, William Tennent, George Whitefield, and others.

The American Revolution brought the dissolution of official ties to British Anglicanism. Many Protestant sects emerged, including ones specifically for African Americans. No longer bound by English license laws, American printers produced Bibles, although importation of English and continental imprints continued. In general, Christian denominations used books and serials to expand their programs.

The 19th-century brought expansion and further denominational proliferation, often following revivals and controversies. Historian Jon Butler has estimated that Americans built 40,000 churches between 1820 and 1860. In addition, individuals with or without affiliation to specific denominations also preached as itinerants. Clergymen such as Henry Ward Beecher, Adoniram Judson, and Charles Grandison Finney became prominent and sometimes controversial. Women such as Salome Lincoln and Sojourner Truth are examples of the tiny minority of women preachers.

Christian evangelicals administered many social programs for both conversion and philanthropy. Members of the Society for the Propagation of the Gospel in Foreign Parts, founded in 1701, sought to christianize the Native Americans. Later Americans served as missionaries both at home and abroad. In addition, the practice of Christianity led many men and women to participate in voluntary organizations founded to reform society – ranging from the abolition of slavery to temperance.

Through all periods of Anglo-American history, Christianity has dominated, and often overshadowed the presence of Jews, Muslims, free thinkers, and others. Within Christianity, Protestant writers frequently have voiced anti-Catholic sentiments either overtly or covertly. Both Christians and non-Christians have practiced other forms of spirituality, such as astrology and dream interpretation, as evidenced by occult literature and references to the occult in other publications. In general, few items in the collection are entirely devoid of references to religion or spirituality.