Considered to be Van der Weyden's masterpiece, Descent from the Cross depicts the crucified Christ being lowered from the cross by Joseph of Arimathea and Nicodemus. Packed into the shallow composition are several other figures, including Mary Cleophas, John the Evangelist, Mary Salome, the Virgin Mary, and Mary Magdalene. 

This painting is oil on oak panel and is in  Museo del Prado, Madrid, Spain.

This work was created in the same period that Van der Weyden was completing his apprenticeship with Robert Campin, whose influence can be felt, for instance, in the hard surfaces, precise details, and taut linearity of the figures. All the elements of this painting are intended to affect the viewer in an immediate, viscerally emotional way. This includes the gestures and expressions of grief each of the figures displays and the parallels between Mary's body as she swoons and the lifeless body of her son. These details exemplify the concept of the "imitation of Christ" central to the Modern Devotion movement of the period that encouraged followers to feel and identify directly with Christ's suffering. Even the tightly compressed space and spatial and conceptual ambiguities in the image enhance the immediacy and presence of the figures.

The Descent from the Cross also had an immediate impact on other artists, many of whom in subsequent years emulated or directly copied the composition or its figures. The first copy, known as the Edelheere triptych (Museum M, Leuven), was made by an unknown artist as early as 1435, and de Vos lists fifteen other existing versions or interpretations in paintings and prints, among only the most important examples.