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The unique circumstances of leaving home for college place specific pressures on adolescents and their families. Disruptions in behavior and mood that occur in relation to the adolescent's leaving home for college represent a form of separation anxiety associated with the transition from middle to late adolescence. The struggle to separate from childhood and family can be problematic even for the most sophisticated, academically talented and self-assured adolescent. For some adolescents the re-emergence of separation fears may suggest earlier unresolved separation-individuation issues. Often these adolescents have reached an impasse as represented by their inability to grieve the loss of childhood ties to their family of origin. Some present with complicated developmental histories involving various neurodevelopmental (e.g., developmental deficits, learning disabilities) and environmental traumas (e.g., family conflict, divorce, domestic violence, physical and sexual abuse) that can interfere with their ability to negotiate a more autonomous self. Clinical material from four treatment cases will illustrate how these disruptions are manifested within the context of the middle adolescent's struggle to master previously unresolved separation-individuation issues. The author describes brief psychotherapeutic interventions that focus on helping these adolescents resolve their conflictual separation feelings and to facilitate their transition to late adolescence.