This painting is the culmination of a series of studies and versions of the same Holy family theme in drawings and cartoons by Leonardo. The composition appears to be similar to that of a cartoon (now lost but known through verbal descriptions) executed in 1501 in preparation for an altarpiece for the Giacomini Tebalducci Chapel in the church of Santissima Annunziata, Florence, which was exhibited to the public in the same church to great acclaim.
The Madonna and Child with St. Anne and St. John the Baptist, (also known as the Burlington Cartoon, National Gallery, London) represents the same family group in a variant of the same composition in what appears to be an unused cartoon drawing.