one of the three leading composers (with Jakob Obrecht and Josquin des Prez) of the Flemish school in the late 15th century.

A pupil of Florentine organist Antonio Squarcialupi, he taught in the household of Lorenzo de' Medici (Medici, Lorenzo de') in Florence (c. 1484–92) and set to music some of Lorenzo's own carnival songs. He apparently left Florence during the Medicean exile, entering the service of the emperor Maximilian I about 1494; in 1497 he was appointed court composer. Between 1497 and 1514 he travelled extensively, finally settling in Florence.

Isaac's main publications were a collection of masses (1506) and the posthumous Choralis Constantinus (1550–55), one of the few complete polyphonic settings of the Proper of the Mass for all Sundays (and certain other feasts); it also contains five settings of the Ordinary. At least in part the work was commissioned for the diocese of Constance in 1508 and employs plainsongs unique to the Constance liturgy. Isaac left his great monument unfinished; it was completed by his pupil Ludwig Senfl.

In his sacred music Isaac treats the cantus firmus (fixed melody) resourcefully, placing the chant in any voice or sharing it between two parts, either in long notes or embroidered with shorter notes. He also uses it as a thematic basis for composing contrapuntal imitations, a technique that came to dominate 16th-century music.

He wrote about 40 secular songs. His Italian frottole (frottola) (simply accompanied songs) have charming treble melodies. His polyphonic German lieder normally present the tune in the tenor but, unlike many contemporary lieder, do not cadence into several sections. His famous “Innsbruck, ich muss dich lassen” (“Innsbruck, I must leave you”) recalls the style of the simpler frottola. This song was later reworked as a chorale, “O Welt 【“World”】, ich muss dich lassen,” familiar through arrangements by J.S. Bach and by Brahms.

His Missa carminum, motets from Choralis Constantinus, music for the court of Lorenzo de' Medici, and secular works Virgo prudentissima have been recorded.