Directional selectivity, in which neurons respond preferentially to one direction of movement ("preferred") over the opposite direction ("null"), is a critical computation that is found in the nervous systems of many animals. Here we show the first experimental evidence for a correlation between differences in short-term depression and direction-selective responses to moving objects. As predicted by quantitative models, the observed differences in the time courses of short-term depression at different locations within receptive fields were correlated with measures of direction selectivity in awake, behaving weakly electric fish (Apteronotus leptorhynchus). Because short-term depression is ubiquitous in the central nervous systems of vertebrate animals, it may be a common mechanism used for the generation of directional selectivity and other spatiotemporal computations.