We present a generalized reverse correlation technique that can be used to estimate the spatio-temporal receptive fields (STRFs) of sensory neurons from their responses to arbitrary stimuli such as auditory vocalizations or natural visual scenes. The general solution for STRF estimation requires normalization of the stimulus-response cross-correlation by the stimulus autocorrelation matrix. When the second-order stimulus statistics are stationary, normalization involves only the diagonal elements of the Fourier-transformed auto-correlation matrix (the power spectrum). In the non-stationary case normalization requires the entire auto-correlation matrix. We present modelling studies that demonstrate the feasibility and accuracy of this method as well as neurophysiological data comparing STRFs estimated using natural versus synthetic stimulus ensembles. For both auditory and visual neurons, STRFs obtained with these different stimuli are similar, but exhibit systematic differences that may be functionally significant. This method should be useful for determining what aspects of natural signals are represented by sensory neurons and may reveal novel response properties of these neurons.