Depersonalization and derealization, encapsulated in the formal diagnosis of Depersonalization/derealization disorder (DDD), present profound challenges in psychiatric practice. This chapter delves into the intricate neurobiological underpinnings of DDD, examining its genesis from a transient response to an enduring disorder. Exploring the link between trauma and dissociation highlights the amygdala’s pivotal role in modulating emotional reactions and the prefrontal cortex’s inhibitory influence on limbic activity. Structural changes, including alterations in cortical thickness and white matter connectivity, provide insights into the disorder’s diverse symptomatology. Interoception, the perception of internal bodily sensations, plays a crucial role in the disorder, as it integrates physiological experiences into one’s overall self-awareness. Furthermore, the interplay of several large-scale brain networks sheds light on the intricate mechanisms governing self-representation and attentional processes. Elucidating these neurobiological pathways paves the way for a deeper understanding of DDD and informs therapeutic interventions aimed at restoring holistic well-being for affected individuals.