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This paper describes an algorithm to continually and accurately estimate the absolute location of a diagnostic or surgical tool (such as a laser) pointed at the human retina, from a series of image frames. We treat the problem as a registration problem using diagnostic images to build a spatial map of the retina and then registering each online image against this map. Since the image location where the laser strikes the retina is easily found, this registration determines the position of the laser in the global coordinate system defined by the spatial map. For each online image, the algorithm computes similarity invariants, locally valid despite the curved nature of the retina, from constellations of vascular landmarks. These are detected using a high-speed algorithm that iteratively traces the blood vessel structure. Invariant indexing establishes initial correspondences between landmarks from the online image and landmarks stored in the spatial map. Robust alignment and verification steps extend the similarity transformation computed from these initial correspondences to a global, high-order transformation. In initial experimentation, the method has achieved 100 percent success on 1024 × 1024 retina images. With a version of the tracing algorithm optimized for speed on 512 × 512 images, the computation time is only 51 milliseconds per image on a 900MHz PentiumIII processor and a 97 percent success rate is achieved. The median registration error in either case is about 1 pixel.