Over the course of the 11th and particularly the 12th centuries, Genoa became the dominant naval force in the Western Mediterranean, as its erstwhile rivals Pisa and Amalfi declined in importance. Genoa (along with Venice) succeeded in gaining a central position in the Mediterranean slave trade at this time.

After the capture of Antioch on May 3, 1098, Genoa forged an alliance with Bohemond of Taranto, who became the ruler of the Principality of Antioch. As a result, he granted them a headquarters, the church of San Giovanni, and 30 houses in Antioch. On May 6, 1098 a part of the Genoese army returned to Genoa with the relics of Saint John the Baptist, granted to the Republic of Genoa as part of their reward for providing military support to the First Crusade. Many settlements in the Middle East were given to Genoa as well as favorable commercial treaties.

Genoa later forged an alliance with King Baldwin I of Jerusalem (reigned 1100–1118). In order to secure the alliance Baldwin gave Genoa one-third of the Lordship of Arsuf, one-third of Caesarea, and one-third of Acre and its port's income. Additionally the Republic of Genoa would receive 300 bezants every year, and one-third of Baldwin's conquest every time 50 or more Genoese soldiers joined his troops.

The Republic's role as a maritime power in the region secured many favorable commercial treaties for Genoese merchants. They came to control a large portion of the trade of the Byzantine Empire, Tripoli (Libya), the Principality of Antioch, Cilician Armenia, and Egypt. Not all of Genoa's merchandise was so innocuous, however, as medieval Genoa became a major player in the slave trade. Although Genoa maintained free-trading rights in Egypt and Syria, it lost some of its territorial possessions after Saladin's campaigns in those areas in the late 12th century.