There is a family of difficult image-processing scenarios which involve seeking out and quantifying minute changes within a sequence of near-identical images. Traditionally these have been dealt with by carefully registering the images in terms of position, orientiation and intensity, and subtracting them from some template image. However, for critical measurements, this approach breaks down if the point-spread-functions (PSFs) vary even slightly from image to image. Subtraction of registered images whose PSFs are not matched leads to considerable residual structure, which may be mistakenly interpreted as real features rather than processing artefacts. In astronomy, software known as ISIS' has been developed to fully PSF-match image sequences and to facilitate their analysis. We show here the tremendous improvement in detection rates and measurement accuracy which ISIS has afforded in our program for the study of rare variable stars in dense, globular star clusters. We discuss the genesis from this work of our new program to use ISIS to search for extra-solar planets in transit across the face of stars in such clusters. Finally we illustrate an application of ISIS in the industrial imaging sector,showing how it can be used to detect minute faults in images of products.