The combination of targeted gene knockout studies in animals and human mutational analysis has demonstrated the key role of the IGF system in mammalian growth, both in utero and postnatally. The concept of IGF deficiency as a diagnostic category for children with growth failure first was proposed in the mid 1990s, and has gained support through the demonstration of patients with mutations in key components of the growth hormone (GH)-IGF axis, as well as the widespread use of IGF-I assays for evaluating short stature. The US Food and Drug Administration has approved IGF-I therapy for treating children who have severe primary IGF deficiency, defined as a height SD score < or =-3 and a serum IGF-1 SD score < or =-3, normal serum GH. Recent studies have demonstrated the efficacy and safety of IGF-I therapy in such patients, and investigations are in progress to determine optimal dosing. The availability of IGF-I therapy thus has expanded the therapeutic tool chest available to endocrinologists caring for children who have growth failure.