Growth hormone and growth hormone receptor are expressed in many extrapituitary tissues, permitting autocrine/paracrine activity. Autocrine growth hormone has regulatory functions in embryonic development, cellular differentiation and proliferation and is reported to be involved in the development and metastasis of tumor cells. To understand the principles of transport and signaling of autocrine growth hormone and growth hormone receptor, we used a model system to express both proteins in the same cell. Our experiments show that growth hormone binds the growth hormone receptor immediately after synthesis in the endoplasmic reticulum and facilitates maturation of growth hormone receptor. The hormone-receptor complexes arrive at the cell surface where exogenously added growth hormone is unable to bind these receptors. Autocrine growth hormone activates the growth hormone receptors, but signal transduction only occurs after exiting the endoplasmic reticulum. This model study explains why autocrine growth hormone-producing cells may be insensitive for growth hormone (antagonist) treatment and clarifies autocrine signaling events.