Perceptual disturbances occur across various sensory domains and contribute to significant suffering in numerous psychiatric and neurological conditions. Despite decades of research into the neural mechanisms underlying these distressing experiences, progress has been relatively limited. Here we explore the potential of layer-specific fMRI to enhance our understanding of these phenomena. We posit that perceptual disturbances can stem from alterations in the neural integration of internally generated signals–such as memory, imagination, prediction, and expectations–with sensory evidence being used to optimize inferences about the world. Emerging evidence suggests that these key computations are distributed across different cortical layers, highlighting the utility of layer-specific imaging in identifying the mechanisms driving such disruptions. We review recent findings that underscore the promise of layer-specific fMRI in elucidating these neural processes and discuss how pharmacological layer-specific fMRI could further advance this understanding. Finally, we address the current limitations of layer-specific fMRI and the progress made toward overcoming these challenges.