Mapping images into the same anatomical coordinate system via image registration is a fundamental step when studying physiological processes, such as brain development. Standard registration methods are applicable when biological structures are mapped to the same anatomy and their appearance remains constant across the images or changes spatially uniformly. However, image sequences of animal or human development often do not follow these assumptions, and thus standard registration methods are unsuited for their analysis. In response, this dissertation tackles the problems of i) registering developmental image sequences with spatially non-uniform appearance change and ii) reconstructing a coherent 3D volume from serially sectioned images with non-matching anatomies between the sections. There are three major contributions presented in this dissertation. First, I develop a similarity metric that incorporates a time-dependent appearance model into the registration framework. The proposed metric allows for longitudinal image registration in the presence of spatially non-uniform appearance change over time—a common medical imaging problem for longitudinal magnetic resonance images of the neonatal brain. Next, a method is introduced for registering longitudinal developmental datasets with missing time points using an appearance atlas built from a population. The proposed method is applied to a longitudinal study of young macaque monkeys with incomplete image sequences. The final contribution is a template-free registration method to reconstruct images of serially sectioned biological samples into a coherent 3D volume. The method is applied to confocal fluorescence microscopy images of serially sectioned embryonic mouse brains.