The United States has maintained an official presence in South Africa since 1799, when an American consulate was opened in Cape Town. The U.S. embassy is located in Pretoria, and consulates general are in Johannesburg, Durban, and Cape Town. Americans and South Africans also have many nongovernmental ties; for example, black and white American missionaries have a long history of activity in South Africa.

From the 1970s through the early 1990s, U.S.-South Africa relations were severely affected by South Africa's racial policies. However, since the abolition of apartheid and democratic elections of April 1994, the United States has enjoyed an excellent bilateral relationship with South Africa. During President Nelson Mandela's October 1994 State visit to the United States, the U.S.-South Africa Binational Commission was created. The commission is designed to promote cooperation between the two countries in such areas as trade and investment, agriculture, human resources development and education, conservation and the environment, energy and technology, and defense. In 2002, the U.S.-South Africa Cooperative Forum replaced the Binational Commission as a principal conduit to promote bilateral cooperation between the two countries. Through the U.S. Agency for International Development (USAID), the United States also provides assistance to South Africa to help it meet its development goals. Peace Corps volunteers began working in South Africa in 1997.