Ghrelin, a natural GH secretagogue (GHS) acylated peptide, and cortistatin (CST), a natural SRIF-like peptide, interfere with neoplastic growth in different cancers. We tested forty-one lung carcinomas and the H345 small cell lung carcinoma (SCLC) cell line by RT-PCR to investigate the presence of ghrelin and CST and related receptors, including type 1a GHS receptor (GHS-R1a), all SRIF-receptor subtypes (sst 1-5) and MRGX2. Moreover, the presence of ghrelin and CST peptides was studied in both tumors and H345 cells. Ghrelin and CST mRNA were present in the majority of tested tumors, but ghrelin and CST proteins were revealed only in tumors with a neuroendocrine phenotype. All the receptors mRNA had a heterogeneous expression without correlation between ghrelin (or CST) and their receptor distribution. All the transcripts, but not GHS-R1a, were expressed in H345 cells. However, ghrelin and desacyl ghrelin induced in vitro a dose-dependent inhibition on the H345 cell proliferation and increased apoptosis. Conversely, neither CST nor SRIF affected H345 cell growth, despite the presence of their specific receptors. The anti-proliferative and the pro-apoptotic effects of ghrelin were consistent with binding experiments on H345 cell, where either acylated or des-acylated ghrelin recognized a common binding site. In conclusion, the present study indicates that: a) ghrelin and CST mRNAs are expressed in lung cancers, although some neuroendocrine tumors contain detectable amounts of the peptides; b) GHSR-1a mRNA is present exclusively in neuroendocrine tumors, whereas MRGX2 mRNA (but not peptide) is expressed in all histological types; c) both ghrelin forms inhibit H345 cell proliferation, both directly and enhancing apoptosis, despite the absence of GHS-R1a, whereas CST and its receptors do not interfere with cell growth.