Spain was prevented from pursing African colonies by the Treaty of Tordesillas, which was granted to them so they could secure American colonies without competition from Portugal. Lacking any Eastern African colonies, Spain was only able to access East Asia via the dangerous Cape Horn passage. After the Zaragoza line was established, it was realized that much of the land in the East was within Portuguese territory. The Portuguese were necessary to fund the increasingly expensive Italian wars (and following several Spanish defeats in Asia), leading the Spanish to nominally uphold Zaragoza. The Philippines were the major exception to this rule, being conquered as a Spanish colony under Mexico to facilitate Spanish-Asian trade.

The Middle East was a entirely off limits for all European powers, since the Ottoman Empire was reaching the apogee of its power by the mid-16th century. Portugal and the Ottomans would clash with each other over control of the Red Sea and Indian ocean numerous times during the 16th and early 17th centuries. The Spanish Empire would clash with the Ottomans in the Mediterranean as part of a greater Habsburg coalition, famously at Malta, Lepanto, and Fez.