Topographic mapping of neural circuits is fundamental in shaping the structural and functional organization of brain regions. This developmentally important process is crucial not only for the representation of different sensory inputs but also for their integration. Disruption of topographic organization has been associated with several neurodevelopmental disorders. The aim of this review is to highlight the mechanisms involved in creating and refining such well-defined maps in the brain with a focus on the Eph and ephrin families of axon guidance cues. We first describe the transgenic models where ephrin-A expression has been manipulated to understand the role of these guidance cues in defining topography in various sensory systems. We further describe the behavioral consequences of lacking ephrin-A guidance cues in these animal models. These studies have given us unexpected insight into how neuronal activity is equally important in refining neural circuits in different brain regions. We conclude the review by discussing studies that have used treatments such as repetitive transcranial magnetic stimulation (rTMS) to manipulate activity in the brain to compensate for the lack of guidance cues in ephrin-knockout animal models. We describe how rTMS could have therapeutic relevance in neurodevelopmental disorders with disrupted brain organization.