Cardiac motion is one of the main sources of artifacts in epifluorescence imaging experiments. It can cause significant error in electrophysiological measurements such as action potential duration. We present a novel approach that uses image registration based on maximization of mutual information to correct for in-plane cardiac motion in such experiments. The approach is relatively fast (a few seconds per frame) and is performed entirely post acquisition. The image registration approach is an alternative to traditional approaches such as mechanical restraint of the heart or addition of chemical uncouplers. Our results show that the image registration method significantly reduces motion-related artifacts in experimental data.