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For nearly a century, the painting venerated as Notre Dame de Grâce de Cambrai has been an exemplar in studies of artistic transmission between northwestern Europe and Byzantium. While scholars note in passing that the painting is Italian, little attention has been paid to the role played by its Trecento origins in shaping its unusual formal qualities and later celebration in the North. This paper first explores the panel’s interweaving of Tuscan, southern Italian and Balkan elements and their possible relationship to papal and Angevin projects previously elided through the simple sobriquet Italo-Byzantine. It then turns to the panel’s later French reception to suggest that parallels to Roman icons attributed to St. Luke, rather than perceived Byzantine origins, lay at the heart of the panel’s fifteenth-century cult. These moments reveal the blurred boundaries of medieval ‘Italy’ and the intersections of ritual and visual translation as interpretive modes.