Ghrelin is a 28 amino acid acylated peptide, which is produced and secreted by X/A-like enteroendocrine cells of the stomach. We have recently demonstrated that ghrelin is expressed by various immune cells including T- and B-lymphocytes, monocytes and neutrophils. These immune cells have also been shown to express the ghrelin receptor, namely the growth hormone secretagogue receptor (GHS-R). In the present study, we have investigated the effects of ghrelin on T cell proliferation and its signaling through its cell surface receptor. We have found that ghrelin induces a modest increase in the proliferation of murine CD4+ T cells and T-cell lines. Western blot experiments have demonstrated that GHS-R ligation activates the external receptor activated kinases (ERK1/2) and Akt signaling pathways in a dose-dependent fashion. Moreover, we have also revealed the involvement of the PKC pathway in the phosphorylation of ERK1/2. The pro-proliferative effects of ghrelin through ERK1/2 appears to be mediated through the regulation of the expression of cell cycle proteins, cyclin D1, CDK4, cyclin E and CDK2 as well as Rb. Together, these data suggest that ghrelin promotes the cell proliferation of T cell via the activation of the PKC, PI-3-K, Akt and Erk1/2 signaling pathways and that this GHS-R signal appears to be essential but not sufficient for cell cycle progression.