These letters concern various scientific subjects, such as fishes, insects, snakes, mice, fossils, and mosses. Other subjects include learned institutions, notably the Smithsonian Institution and the Academy of Natural Sciences of Philadelphia, and men of science. Correspondents include S. S. Haldeman, Walter J. Hoffman, Spencer F. Baird, Edward D. Cope, and Leo Lesquereux.

Principal correspondents in the lettes of John Fries Frazer include Alexander Dallas Bache, Louis Agassiz, Joseph Henry, and Titian Ramsay Peale who discuss mainly general scientific topics, although personal and family matters are discussed with Bache. Topics include the University of Pennsylvania, boiler explosions, chemistry, education, the National Academy of Sciences, the Smithsonian Institution, fossils, magnetism, solar eclipses, the American Philosophical Society, weights and measures, the U.S. Coast and Geodetic Survey, scientific instruments, the American Civil War, electricity, the United States Mint, the Franklin Institute, scientists of the period, natural history, and publications.

This is a small but diverse collection documenting Wheatley's interests in mines and mining technology, paleontology, mineralogy, and shells. There are sketches of Wheatley's mine near Phoenixville, Pennsylvania; estimates of costs of machinery, and a list of furnace products sent to the Centennial Exposition.

These papers reflect Isaac Hays' interests and activities in the medical profession and as an editor. His interest in paleontology, especially in the controversy with G. W. Featherstonhaugh, is also represented. There is one separate volume (77 letters) containing correspondence about natural history and naturalists, written to Hays by C. L. Bonaparte, George Ord, Thomas Say, and Charles A. Lesueur. The correspondence in the larger collection, however, contains much material on the American Journal of the Medical Sciences, particularly illuminated in the correspondence with John D. Godman. The I. Minis Hays material consists of letters from doctors, relating to medicine and medical publications and editing, as well as medical organizations. Most significant of the correspondence is that with John Shaw Billings (ca. 60 letters).