The naval strength of the Ottomans has become formidable in the reign of Süleyman.

Suleiman the Magnificent had in 1653 ordered Hayreddin Barbarossa, whom he had summoned from Algiers, to build a large war fleet in the arsenal of Constantinople.

Altogether, seventy galleys had been built during the winter of 1533–1534.

With this fleet, Barbarossa conducts aggressive raids along the coast of Italy, until he conquers Tunis on  August 16, 1534, ousting the local ruler, heretofore subservient to the Spanish, Muley Hasan.

Barbarossa thus establishes a strong naval base in Tunis that can be used for raids in the region, and on nearby Malta. 

Charles V, one of the most powerful men in Europe at this time, assembles a large army of some thirty thousand soldiers, seventy-four galleys, and three hundred ships—including the Santa Anna and Portuguese galleon São João Baptista, also known as Botafogo (Spitfire) and the most powerful ship in the world at the time, with three hundred and sixty-six bronze cannons—to drive the Ottomans from the region.

The expense involved for Charles V is considerable, and at one million ducats is on par with the cost of Charles' campaign against Suleiman on the Danube.

Unexpectedly, the funding of the conquest of Tunis comes from the galleons sailing in from the New World, in the form of a two million gold ducats treasure extracted by Francisco Pizarro in exchange for his releasing of the Inca king Atahualpa (whom he nevertheless executed on August 29, 1533).

Despite a request by Charles V, Francis I has denied French support to the expedition, explaining that he is under a three-year truce with Barbarossa following the 1533 Ottoman embassy to France.

Francis I is also under negotiations with Suleiman the Magnificent for a combined attack on Charles V, following the 1534 Ottoman embassy to France.

Francis I only agrees to Pope Paul III's request that no fight between Christians occur during the time of the expedition.

The Knights of Malta, who have organized piratical raids against Ottoman ships, capture Tunis and Goletta in 1535 with the aid of Doria and the imperial fleet.