IGF-IR (Insulin-like Growth Factor I Receptor), also known as CD221, is a ubiquitously expressed heterotetrameric transmembrane glycoprotein consisting of two alpha and two beta subunits. It binds IGF-I with high affinity, IGF-II with lower affinity, and Insulin with lowest affinity. IGF-I R/Insulin R hybrids respond primarily to IGF-I and may downregulate cellular responses to Insulin. IGF signaling is also modulated by IGF binding proteins and the scavenger receptor, IGF-II R. Mice lacking IGF-I R show intrauterine growth deficiency and die at birth due to respiratory failure, and IGF-I R mutations in humans can retarded pre- and postnatal growth. IGF-I and its receptor are particularly important for neurogenesis, with deficiency producing microcephaly and learning disorders. IGF-IR expression on human embryonic stem cells is important for their survival and clonogenicity.