The acute metabolic actions of purified human growth hormone (GH) were first documented in adult hypopituitary patients more than 50 years ago, and placebo-controlled long-term GH trials in GH-deficient adults (GHDA) surfaced in 1989 with the availability of biosynthetic human GH. Untreated GHDA is associated with excess morbidity and mortality from cardiovascular disease and the phenotype includes fatigue, reduced aerobic exercise capacity, abdominal obesity, reduced lean body mass, osteopenia and elevated levels of circulating cardiovascular biomarkers. Several of these features reverse and normalize with GH replacement. It remains controversial whether quality of life, assessed by questionnaires, improves. The known side effects are fluid retention and insulin resistance, which are reversible and dose dependent. The dose requirement declines markedly with age and is higher in women. Continuation of GH replacement into adulthood in patients with childhood-onset disease is indicated, if the diagnosis is reconfirmed. GH treatment of frail elderly subjects without documented pituitary disease remains unwarranted. Observational data show that mortality in GH-replaced patients is reduced compared to untreated patients. Even though this reduced mortality could be due to selection bias, GH replacement in GHDA has proven beneficial and safe.