Recombinant human growth hormone (GH) has been in use for over 30 years, and its indications have gradually expanded from the classical replacement therapy in GH deficiency (GHD) to pharmacological therapy in patients with normal GH secretion. The insulin-like growth factor-I (IGF-I ) is closely GH dependent and is the effector of GH biological actions in peripheral tissues. Since IGF-I has potent mitogenic and antiapoptotic effects, the use of GH, especially outside GHD, has raised safety concern regarding cancer risk. The results of experimental, epidemiological and observational studies are not univocal and a number of biases and confounders affect the interpretation of data. The aim of this review is to critically review the data linking GH therapy during childhood with cancer risk, highlighting strengths and weaknesses of the available evidence.