The geographic coverage of the division's special collections is worldwide, but its primary focus is North and South America, with the strongest holdings in the general subjects of discovery and exploration, settlement, and military campaigns.

In 1949, Lessing J. Rosenwald donated six rare Renaissance maps, including Diego Gutiérrez's celebrated map of the Western Hemisphere entitled Americae sive qvartae orbis partis nova et exactissima descriptio (1562). The other gifts include André Thevet's equally rare Le Novveav monde descovvert et illvstre de nostre temps, published in Paris in 1581; Franz Hogenberg's Americae et proximarvm regionvm orae descriptio (1589); Paolo Forlani's world map, Vniversale descrittione di tvtta la terra conoscivta fin qvi, engraved by Ferrando Bertelli (1565); and Gabriel Tatton's Maris Pacifici, engraved by Benjamin Wright (1600). Other significant collections that pertain to the discovery and exploration of America include materials collected by Henry Harrisse, Johann Georg Kohl, and Woodbury Lowery.

Several presidents of the United States displayed some skill as cartographers, or even began their careers as surveyors, such as George Washington, Thomas Jefferson, and Millard Fillmore. The collections of two twentieth-century presidents, Theodore Roosevelt and Woodrow Wilson, reflect the expanding role of the presidency on the international scene. Other presidents associated with maps in the special collections include John Quincy Adams, James Buchanan, Abraham Lincoln, William McKinley, James Monroe, and Franklin Roosevelt.

One of the great treasures of the division is Pierre Charles L'Enfant's original plan for the capital of the United States, which was compiled under the direction of George Washington and extensively annotated by Thomas Jefferson. Entitled Plan of the City Intended for the Permanent Seat of the Government of the United States, L'Enfant's plan forms the cornerstone of the Library's unrivaled collection of maps and atlases of the city of Washington, D.C.

The bequest of Henry Harrisse, who was both a collector and a student of the exploration of America, included fourteen manuscript maps drawn by Johannes Vingboons, cartographer to the Prince of Nassau, for the West India Company of Holland. One of these, which was entitled Manatvs and was "Drawn on the Spot" in 1639, is the earliest cartographic depiction of Manhattan Island. Another noteworthy map bequeathed by Harrisse is a map on vellum entitled Description du pais des Hurons by St. Jean de Brébeuf, illustrating the location of American Indian tribes and Jesuit missions in the vicinity of Lake Huron.

Complementing Harrisse is the Johann Georg Kohl Collection of 474 annotated manuscript facsimile maps relating to the discovery and exploration of the New World from 1500 to 1834. These maps were copied by the nineteenth-century German geographer Johann Georg Kohl from "old books" and collections in Germany, France, and England.

For the student of nineteenth-century exploration of the American West, the division has particularly rich holdings. The Lewis and Clark Collection is indispensable for understanding the early mapping of this region. Transferred in 1925 from the files of the Office of Indian Affairs, Department of the Interior, the collection consists of twelve manuscript maps associated with the planning of the Lewis and Clark overland expedition to the mouth of the Columbia River from 1803 to 1806 and activities relating to William Clark's official duties as superintendent of Indian Affairs at St. Louis from 1807 to 1813 and as governor of the Missouri Territory. A related but no less valuable item from the Vault Map Collection is Robert Frazer's large manuscript Map of the discoveries of Capt Lewis & Clark from the Rockey mountain and the River Lewis to the Cap of Disappointement or the Coloumbia River At the North Pacific Ocean. A member of the Corps of Discovery, Frazer prepared this map in 1806 to accompany his own journal of the expedition, which was never published. Later, the map came into the possession of John Henry Alexander, the first Maryland state cartographer, and was obtained in 1922 by the Library from the estate of Alexander's son.

Much of the trans-Mississippi west was explored and mapped by military officers of the U.S. Army's Corps of Topographical Engineers and, after the Civil War, by civilian scientists of the Interior Department whose final reports and maps were published by Congress.

Maps and charts of Latin and South America are well represented. The oldest and most remarkable is a land litigation map of Oztoticpac, a royal Aztec estate in the city of Texcoco near present-day Mexico City. Other milestones of Spanish colonial cartography in Latin America include Juan de la Cruz Cano's rare Mapa geográfico de America meridional (Madrid, 1775), an eight-sheet wall map whose sale was suppressed by Spanish authorities shortly after publication; William Faden's facsimile of the 1775 Cruz Cano map published in 1799 in London at the request of Thomas Jefferson; and Nicolas de Lafora's manuscript copy of Mapa de toda la frontera de los dominios del rey en la America septentrional, originally compiled in 1771 to show Mexico's northern frontier. Another manuscript version of Lafora's map is part of the Gen. Peter H. Hagner Collection.

Special collections that relate primarily to Latin and South America were assembled by John Barrett, director of the Pan American Union, 1894 to 1920; the Panama Canal Zone Library-Museum; the Portuguese-Spanish Boundary Commission; the Maggs Collection of early Spanish nautical charts; and Ephraim George Squier, an American journalist engaged in diplomatic and archeologic work in Central America and Peru from 1849 to 1865.