Growth hormone (GH) is a powerful metabolic hormone that regulates fuel homeostasis through its protein anabolic and lipolytic actions. The introduction of recombinant human GH has expanded the narrow indication of treating children with severe GH deficiency (GHD) to include a broader target population of children with growth retardation and short stature and adults with hypopituitarism and severe GHD. Furthermore, because children continue to receive GH replacement therapy into adult life, the duration of treatment exposure has increased and the safety of long-term GH treatment has become increasingly important. This is of particular concern given that GH-deficient children and adults may be more vulnerable to the mitogenic stimuli of GH and insulin-like growth factor-1, both because of the underlying cause of GHD and also because of previous treatment such as radiotherapy and chemotherapy. This review focuses on the safety of treating adults with severe GHD, with specific emphasis on dose regimens, carbohydrate metabolism, neoplasia, and morbidity and mortality. Available experience from long-term replacement therapy, studies using supraphysiological doses of GH in adults and lessons learned from patients with acromegaly who have high endogenous GH levels over many years, is considered.