The ability of growth hormone (GH) to induce adipose tissue lipolysis has been known for over five decades; however, the molecular mechanisms that mediate this effect and the ability of GH to inhibit insulin-stimulated glucose uptake have scarcely been documented. In this same time frame, our understanding of adipose tissue has evolved to reveal a complex structure with distinct types of adipocyte, depot-specific differences, a biologically significant extracellular matrix and important endocrine properties mediated by adipokines. All these aforementioned features, in turn, can influence lipolysis. In this Review, we provide a historical and current overview of the lipolytic effect of GH in humans, mice and cultured cells. More globally, we explain lipolysis in terms of GH-induced intracellular signalling and its effect on obesity, insulin resistance and lipotoxicity. In this regard, findings that define molecular mechanisms by which GH induces lipolysis are described. Finally, data are presented for the differential effect of GH on specific adipose tissue depots and on distinct classes of metabolically active adipocytes. Together, these cellular, animal and human studies reveal novel cellular phenotypes and molecular pathways regulating the metabolic effects of GH on adipose tissue.