This chapter assesses Dürer’s relationships to music and musicians during the course of his professional life before investigating aspects of Melencolia I that have especially drawn the attention of musicians. I propose another perspective on the number square in this work based on controversies over tuning systems that were rife in Dürer’s lifetime. I also consider responses to Melencolia I in specific compositions, noting in particular the remarkable number of works bearing the title Melencolia I by recent generations of composers.