Isolated GH deficiency (IGHD) is a distinct picture defined as a condition of GHD not associated with other pituitary hormone deficiencies, with or without an organic lesion. It can be drawn depending on the history, clinical picture, and age of onset of GHD. In childhood, 3 categories of IGHD can be identified: IGHD due to manifest organic alterations of the hypothalamo-hypophyseal system, genetically determined, and idiopathic. Adults with IGHD can also be grouped in those who had prior childhood IGHD, those who acquire IGHD secondary to structural lesions or trauma, and those with idiopathic IGHD. Diagnosis of IGHD in childhood requires clinical and auxological assessment, combined with biochemical tests, neuroradiological and genetic evaluation. In adults there is no single biological marker that offers the same diagnostic usefulness as the growth rate in children, therefore, both a clearly positive GH provocative test and an IGF-I level below the lower limit of normal should be present. Therapeutic response to GH replacement in IGHD is comparably favorable in both adult-onset and childhood-onset and is most likely to benefit those patients who have more severe GHD.