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This case study sketches the trans-professional and transnational careers of two upwardly mobile and cosmopolitan actors in the incoming “Century of the Genoese.” These examples of biography in history are analytically framed within the stream of research on social mobility in medieval and early modern Italy, and then compared with the organizational and institutional behavior of some Atlantic entrepreneurs of the sixteenth century. This framework also takes into account the dualism and transactional focus of the Genoese polity with the aim of reassessing the historical reasoning on entrepreneurship proposed by business historians who responded to the “Schumpeter’s plea” in this regard.