Background: Approximately one in three children and young people with chronic fatigue syndrome (CFS/ME) also have probable depression. Cognitive behaviour therapy (CBT) has a growing evidence base as an effective treatment approach for CFS/ME and for depression in this population. Aims: Given the high degree of co-morbidity, this discussion paper aims to compare and contrast CBT for CFS/ME and CBT for depression in children and young people. Method: The existing literature on CBT for depression and CBT for CFS/ME, in relation to children and young people was reviewed. Results: Whilst there are commonalities to both treatments, the cognitive behavioural model of CFS/ME maintenance includes different factors and has a different emphasis to the cognitive behavioural model of depression, resulting in different intervention targets and strategies in a different sequence. Conclusions: A collaborative, formulation-driven approach to intervention should inform the intervention targets and treatment strategies.