Diagnosis and treatment of patients with hypopituitarism needs careful clinical evaluation and individual optimization. Symptoms of hypopituitarism are variable, often insidious in onset and dependent on the degree of hormone deficiency. Diagnosis of hypopituitarism can be straightforward by measuring reduced basal hormone levels. Frequently, dynamic stimulation tests are indicated in equivocal basal hormone levels or to diagnose partial hormone deficiencies. Knowledge of the use and limitations of these dynamic tests is mandatory for proper interpretation. Hormone replacement therapy should be individualized, taking into account possible interactions. Persisting symptoms and reduced quality of life are frequently reported, explained by, at least in part, intrinsic imperfections of hormone replacement strategies in mimicking normal hormone secretion. In the present overview, the principles of diagnosis and treatment of hypopituitarism are discussed.