Thereafter, Genoa underwent something of a revival as a junior associate of the Spanish Empire, with Genoese bankers, in particular, financing many of the Spanish crown's foreign endeavors from their counting houses in Seville. Fernand Braudel has even called the period 1557 to 1627 the "age of the Genoese", "of a rule that was so discreet and sophisticated that historians for a long time failed to notice it", although the modern visitor passing brilliant Mannerist and Baroque palazzo facades along Genoa's Strada Nova (now Via Garibaldi) or via Balbi cannot fail to notice that there was conspicuous wealth, which in fact was not Genoese but concentrated in the hands of a tightly knit circle of banker-financiers, true "venture capitalists". Genoa's trade, however, remained closely dependent on control of Mediterranean sealanes, and the loss of Chios to the Ottoman Empire (1566), struck a severe blow.

The opening for the Genoese banking consortium was the state bankruptcy of Philip II in 1557, which threw the German banking houses into chaos and ended the reign of the Fuggers as Spanish financiers. The Genoese bankers provided the unwieldy Habsburg system with fluid credit and a dependably regular income. In return the less dependable shipments of American silver were rapidly transferred from Seville to Genoa, to provide capital for further ventures.