The United States first began to take interest in Central, South America, and the Caribbean during the early part of the 19th century. The acquisition of Florida from Spain led to the general assumption that the US would eventually acquire Cuba, as well as other Caribbean countries. During the 1820's, several Latin American countries rebelled against Spanish control. At this point (1823), the US passed the Monroe Doctrine, which warned against European intervention in "any of the American nations that have recently become independent." However, these newly freed countries where heavily under the influence of the British Empire as a result of trading.

Post-Civil War America had its eye on expansion; manifest destiny was the spirit of the day. Once settlers had claimed California, expansionist eyes turned to Latin America. One of the United States' first major attempts at establishing hegemony in this area was the Clayton-Bulwer treaty of 1855. The treaty stated that neither Britain nor the US would unilaterally build a canal in the Central American isthmus. This was an important step for the US, because this agreement marked the first time Britain recognized American interests in Latin America.

Because of its colonial origin, America was initially opposed to the idea of imperialism. However, events in Latin America changed these anti-imperialist ideas. Following the Clayton-Bulwer treaty, the US began to challenge England's commercial dominance of the region. An example of this was the Venezuelan boundary dispute of 1895. The English had discovered gold near the undetermined borders of Venezuela and British Guyana. The British hoped to draw a border that infringed on Venezuela. America set in as a mediator and eventually solved the dispute. Because of this incident, the US passed the Olney Corollary to the Monroe doctrine (named after the man who wrote it). It stated that the US had the right to look after the interests of all groups in the Western Hemisphere. By 1895, America had become the dominant nation of the Western Hemisphere.

Most Americans believed that Cuba would eventually break away from Spain's control and become a US territory (if not a state). However, during the Latin American revolutions of the 1820's, Cuba remained loyal. It wasn't until the end of the century that Cuba began to struggle for independence. 1868 marked the beginning of the ten-year war, in which Cuban planters freed and armed their slaves to fight the Spanish. During this war, Jose Marti, one of the future heroes of the Spanish-American war, was exiled to Spain as a result of revolutionary actions. The ten-year war ended in 1878 with the Zanjon treaty, which didn't grant Cuba independence. America (under the Grant administration) refused to get involved with this war.