The discovery of the New World in 1492 was very significant for the city, which became the European port of departure to America. It was a cosmopolitan and universal. Seville was already late fifteenth century one of the main ports in Castilian trade, mainly with England, Flanders and Genoa. The Muslim minority suffered a blow in 1502 when the Moorish were forced to convert to Christianity, calling Moors who did it, thus achieving religious unity as the basis for national unity.
El Puerto de Indias in Seville had become the major gateway to Latin maintaining artificial monopoly as an entry and exit of the Indies by a seat granted by royal decree. For administration, the Catholic Monarchs established the House of (what is now the Archive of the Indies), from where they were going and recruiting trips, they controlled the wealth that came to America and, together with the University of Merchants, regulating the trade relations, scientific and judicial with the New world.8 This resulted in large urban expansion exceeding 100,000 inhabitants, making it the largest city in Spain and more urbanized at the time, emphasizing its bricked or paved streets.

During the sixteenth century Seville expanded enormously, is the monumental century par excellence of Seville, because thanks to the Guadalquivir River and the port of Seville at that time called India Gate drive the period of greatest splendor after the discovery of America in 1492. In 1502-1503 the Catholic Kings founded the House of Trade (1503) in the Alcazar, to regulate commercial and judicial relations with America, "where they go and hire travel to control the wealth coming from the New World.
The most important buildings of the historic center of this era are: the Cathedral (finished in 1506), Lonja, later, Carlos III ordered their adaptation to accommodate the Archivo de Indias, Giralda (bell tower and Giraldillo: 1560-1568), Hall (1527 -1564), Hospital of the Five Wounds (1544-1601), Church of the Annunciation (1565-1578), Court (1595-1597), the Mint (1585-1587) and other new buildings like the Casa Pilates The Palacio de las Dueñas or the Church of the Savior.
This resulted in a large urban expansion exceeding 100,000 inhabitants, making it the largest city in Spain and more urbanized at the time, emphasizing its bricked or paved streets. Turn became a metropolis with consulates of all countries of Europe, and traders from all over the continent who settled in Sevilla for their businesses. The city became a multicultural center that would help the flowering of the arts, especially architecture, painting, sculpture and literature, thus playing an important role in the Spanish Golden Age. Successful and productive were the soap factories were established in the Triana district and the crafts of silk (for export to Europe) and ceramics, which had more than fifty factories.
Thanks to the patronage of Catherine de Ribera establishing the Hospital of the Five Wounds, to gather in one place the existing health units. Also in the early sixteenth century in Seville have concern with higher education resulted in the founding of the Colegio Santa Maria de Jesús9 by Maese Rodrigo Fernández de Santaella. This institution was the germ of the future University of Seville, which, together with the advent of printing led to the development of a literary world of great importance Seville. Also when the port was home to American geographers and cartographers, as Amerigo Vespucci who died in this city on February 22, 1512. On March 11, 1526 Carlos I married in the city with Isabel of Portugal.