Growth hormone (GH) promotes postnatal human growth primarily by regulating insulin-like growth factor (IGF)-I production through activation of the GH receptor (GHR)-JAK2-signal transducer and activator of transcription (STAT)-5B signaling pathway. Inactivating STAT5B mutations, both autosomal recessive (AR) and dominant-negative (DN), are causal of a spectrum of GH insensitivity (GHI) syndrome, IGF-I deficiency and postnatal growth failure. Only AR STAT5B defects, however, confer additional characteristics of immune dysfunction which can manifest as chronic, potentially fatal, pulmonary disease. Somatic activating STAT5B and JAK2 mutations are associated with a plethora of immune abnormalities but appear not to impact human linear growth. In this review, molecular defects associated with STAT5B deficiency is highlighted and insights towards understanding human growth and immunity is emphasized. •Loss-of-function homozygous STAT5B mutations cause GHI and immune dysfunction•Dominant-negative STAT5B mutations expands the spectrum of STAT5B deficiency•Somatic gain-of-function STAT5B mutations cause hematological malignancies•JAK2 gain-of-function mutations are not associated with growth failure