The original city was located on the left (east) bank of the Ozama River and was called Nueva Isabela in honour of Queen Isabella. It was destroyed by a hurricane, however, and was rebuilt in 1502 at its present location on the right bank of the river. It became the starting point of most of the Spanish expeditions of exploration and conquest of the other West Indian islands and the adjacent mainland. The colony prospered as the seat of government of the Spanish possessions in the Americas until the conquest of Mexico and Peru, after which its importance declined.

Santo Domingo is the industrial, commercial, and financial centre of the country. Its industrial development has been greatly influenced by the construction of hydroelectric dams, which furnish its industries with inexpensive electrical power. The country's most important industries, such as metallurgy, refrigerators, petrochemicals and plastics, cement, textiles, and food processing, are located in Santo Domingo.

Santo Domingo claims the oldest university in the Western Hemisphere: the Autonomous University of Santo Domingo (founded 1538). The city's other educational institutions include the Pedro Henríquez Ureña National University (1966) and a technological university. Cultural institutions include the National Theatre, the music conservatory and the National Symphony Orchestra, the Museum of Dominican Man—important for its pre-Columbian collection—and various public and private libraries, especially the National Library. The two most prominent colonial monuments in Santo Domingo are the cathedral and the palace of Diego Columbus. The cathedral, built in Spanish Renaissance style, dates from 1514. The Columbus Lighthouse (Faro a Colón) reputedly contains the remains of Christopher Columbus (Columbus, Christopher). The city was designated a UNESCO World Heritage site in 1990. Pop. (2002) urban area, 1,887,586.