BACKGROUND: Syndromes characterized by chronic, medically unexplained fatigue, effort- and stress-intolerance, and widespread pain are highly prevalent in medicine. RESULTS: In chronic fatigue syndrome (CFS) and fibromyalgia (FM), various perpetuating factors may impair patients' quality of life and functioning and impede recovery. Although cognitive-behavioral and graded-exercise therapy are evidence-based treatments, the effectiveness and acceptability of therapeutic interventions in CFS/FM may largely depend on a customized approach taking the heterogeneity of perpetuating factors into account. CONCLUSION: Further research should clarify the aim and outcome of different treatment strategies in CFS/FM, as well as the underlying mechanisms of change, including those facilitating neurobiological recovery.