The increased use of aggressive, combined modality therapy for the treatment of head and neck cancer has resulted in a marked increase in acute and late adverse effects. The acute effects of therapy have long been appreciated; however, it is now being recognized that the late effects of therapy result in a significant symptom burden, diminished functional capacity and decreased quality of survivorship. Furthermore, head and neck cancer has historically been considered a locoregional disease that is treated predominantly with locoregional therapy. It is now recognized that there are systemic effects of therapy that need to be considered. Potential systemic effects of therapy include: fatigue, weight loss, nutritional deficiencies, altered physical functioning and mood disorders. It is important for clinicians to be aware of these late effects in order to provide patients with appropriate support services and referrals. This paper examines the global and systemic effects of therapy.