The bond between the Flemish composer Heinrich Isaac (c.1450-1517) and the city of Florence almost symbolizes the encounter between the world of northern polyphony and the civilization of fifteenth-century Italy. In this dissertation, I examine several aspects of this unique encounter -- patronage, musician's personal and social identity, and artistic osmosis. The main aims are a definition of Isaac's integration in Florence, in both biographical and musical terms, and a reconstruction of its evolution in response to the city's changing political scenarios. Chapter 1 consists of a survey of music in the public rituals of late-15th-century Florence and a study of the various forms of Medicean patronage. In Chapter 2, I present the newly discovered records of the payments Isaac made to the Florentine Confraternity of Saint Barbara; I also revise the composer's later Florentine biography for the years 1502-1517 accordingly. The new evidence corroborates the hypothesis that Isaac had chosen Florence as the residence of his last years by 1502, a decision possibly prompted by reasons outside the professional sphere. The third chapter is devoted to the peculiar Missa Misericordias Domini, the Ordinary cycle that perhaps best embodies Isaac's fusion of Franco-Flemish background and Italian indigenous style. My analysis of this work ranges from philological aspects to stylistic matters; among the most interesting points are a new reconstruction of the work's transmission and an interpretation of its musical relationship with the Italian frottola In focho in focho la mia vita passa, the beginning of which is identical to the Mass head motif. This re-examination of Isaac's relationship with Florence sheds new light on the life and work of the most "Italianate" among the late-fifteenth-century Flemish composers, and offers new insights for a more complete investigation of the social and artistic integration of northern composers active in fifteenth-century Italy.