Sub-pixel image alignment estimation is desirable for co-registration of objects in multiple images to a common spatial reference and as alignment input to multi-image processing. Applications include super-resolution, image fusion, change detection, object tracking, object recognition, video motion tracking, and forensics.Information theoretical measures are commonly used for co-registration in medical imaging. The published methods apply Shannon's Entropy to the Joint Measurement Space (JMS) of two images. This work introduces into the same context a new set of statistical divergence measures derived from Fisher Information. The new methods described in this work are applicable to uncorrelated imagery and imagery that becomes statistically least dependent upon co-alignment. Both characteristics occur with multi-modal imagery and cause cross-correlation methods, as well as maximum dependence indicators, to fail. Fisher Information-based estimators, together as a set with an Entropic estimator, provide substantially independent information about alignment. This increases the statistical degrees of freedom, allowing for precision improvement and for reduced estimator failure rates compared to Entropic estimator performance alone.The new Fisher Information methods are tested for performance on real remotely-sensed imagery that includes Landsat TM multispectral imagery and ESR SAR imagery, as well as randomly generated synthetic imagery. On real imagery, the co-registration cost function is qualitatively examined for features that reveal the correct point of alignment. The alignment estimates agree with manual alignment to within manual alignment precision. Alignment truth in synthetic imagery is used to quantitatively evaluate co-registration accuracy. The results from the new Fisher Information-based algorithms are compared to Entropy-based Mutual Information and correlation methods revealing equal or superior precision and lower failure rate at signal-to-noise ratios below one.