To elucidate whether a specific tissue is responsible for the beneficial health and longevity phenotype seen in growth hormone (GH) receptor (R) knockout (GHRKO) mice, the GHR gene was disrupted specifically in insulin sensitive tissues; namely, liver, adipose, and muscle. Furthermore, to investigate if the health- and life-span effects seen in the germline GHRKO mice were replicated when GH action was ablated after puberty; young, adult onset GHRKO mice were produced and characterized. In this review, we summarized the main findings derived from these mouse lines.