Drosophila melanogaster exhibits a robust escape response to objects approaching on a collision course. Although a pair of large command interneurons called the giant fibers (GFs) have been postulated to trigger such behaviors, their role has not been directly demonstrated. Here, we show that escape from visual stimuli like those generated by approaching predators does not rely on the activation of the GFs and consists of a more complex and less stereotyped motor sequence than that evoked by the GFs. Instead, the timing of escape is tightly correlated with the activity of previously undescribed descending interneurons that signal a threshold angular size of the approaching object. The activity pattern of these interneurons shares features with those of visual escape circuits of several species, including pigeons, frogs, and locusts, and may therefore have evolved under similar constraints. These results show that visually evoked escapes in Drosophila can rely on at least two descending neuronal pathways: the GFs and the novel pathway we characterize electrophysiologically. These pathways exhibit very different patterns of sensory activity and are associated with two distinct motor programs.