Chronic traumatic encephalopathy (CTE) is a perplexing condition characterized by a broad and diverse range of neuropathology and psychopathology. While there are no agreed upon or validated clinical criteria for CTE, case series of CTE have described a wide range of neuropsychiatric symptoms that have been attributed to repetitive traumatic brain injuries (rTBI). However, the direct links between the psychopathology of psychiatric and neurological conditions from rTBI to CTE remains poorly understood. Prior studies suggest that repetitive cerebral injuries are associated with damage to neural circuitry involved in emotional and memory processes, but these studies do not offer longitudinal assessments that prove causation. More recent studies on novel targets, such as transmission of misfolded proteins, as well as newly advanced non-invasive imaging techniques may offer more direct evidence of the pathogenesis of CTE by tracing the progression of pathology and display of related behavioral impairments. Understanding this interface in the context of rTBI can play an important role in future approaches to the definition, assessment, prevention, and treatment of CTE and mental illnesses.