Spontaneous molecular oscillations are ubiquitous in biology. But to our knowledge, periodic cell migratory patterns have not been observed. Here we report the highly regular, periodic migration of cells along rectilinear tracks generated inside three-dimensional matrices, with each excursion encompassing several cell lengths, a phenotype that does not occur on conventional substrates. Short hairpin RNA depletion shows that these one-dimensional oscillations are uniquely controlled by zyxin and binding partners α-actinin and p130Cas, but not vasodilator-stimulated phosphoprotein and cysteine-rich protein 1. Oscillations are recapitulated for cells migrating along one-dimensional micropatterns, but not on two-dimensional compliant substrates. These results indicate that although two-dimensional motility can be well described by speed and persistence, three-dimensional motility requires two additional parameters, the dimensionality of the cell paths in the matrix and the temporal control of cell movements along these paths. These results also suggest that the zyxin/α-actinin/p130Cas module may ensure that motile cells in a three-dimensional matrix explore the largest space possible in minimum time.