Cognitive neuroscience can provide novel and interesting techniques for investigating spatial and geographic thinking. However, the incorporation of neuroscientific methods still lacks the theoretical motivation necessary for the progression of geography as a discipline. Rather than reflecting a shortcoming of neuroscience, this weakness has developed from previous attempts to establish a positivist approach to behavioral geography. In this chapter, we will discuss the challenges of establishing a positivist approach in behavioral geography and the current drive to incorporate neuroscientific evidence. Towards this end, we review research in geography and neuroscience. Here, we focus specifically on navigation and large-scale spatial thinking. We argue that research at the intersection of geography and neuroscience would benefit from an explanatory, theory-driven approach rather than a descriptive, exploratory approach. Future collaborations will require additional training for geographers and neuroscientists and the involvement of both disciplines during the early stages of a research program.