The Portuguese have not only monopolized the European spice trade after the conquest of Malacca in 1511 but also meet and trade avidly with Chinese merchants.

When Portuguese under Diogo Lopes de Sequeira had earlier arrived in Malacca in 1509 to open trade relations, he had been supported by the local Chinese merchants there (along with Javanese and Tamil merchants).

Alfonso D'Albuquerque had sent Jorge Álvares to explore northward; his expedition had sailed along the coast of Guangdong in 1513 and hoisted a flag on "Tuen Mun island".

Jorge Álvares had been the first to land on Lintin Island in the Pearl River Delta in May 1513, but it is Rafael Perestrello—a cousin, by marriage, of the famed Christopher Columbus—who becomes the first European explorer to land on the southern coast of mainland China and trade in Guangzhou in 1516, commanding a Portuguese vessel with a crew from a Malaysian junk that had sailed from Malacca.

He provides an enticing report to other Portuguese on the lucrative trade in China.

This prompts Fernão Pires de Andrade to speed up the course of his mission while stalled in Malacca and debate with his crew on whether to go to China or Bengal.

The Portuguese send a large subsequent expedition in 1517 to enter port at Guangzhou to trade with the Chinese merchants here.

During this expedition the Portuguese attempt to send an inland delegation in the name of Manuel I of Portugal to the court of the Zhengde Emperor.

Fernão Pires de Andrade is able to meet the Zhengde Emperor while the latter is touring Nanjing in May 1520.

Pires de Andrade's mission waits in Beijing to meet the Zhengde Emperor once more, but the emperor dies in 1521.

The new Grand Secretary, Yang Tinghe, rejects eunuch influence at court and rejects this new foreign embassy by the Portuguese once Malaccan ambassadors arrive in China damning the Portuguese for deposing their king; the Portuguese diplomatic mission languishes in a Chinese prison where they die.

Simão de Andrade, brother to ambassador Fernão Pires de Andrade, had also stirred Chinese speculation that the Portuguese were kidnapping Chinese children to cook and eat them; Simão had purchased children as slaves who will later be found by Portuguese authorities in Diu, India.

Ming dynasty naval forces fight and repulse Portuguese ships in 1521 at Tuen Mun, where some of the first breech-loading culverins are introduced to China, and again fight off the Portuguese in 1522.