Since the cloning and characterization of the five human somatostatin receptor (SSTR) subtypes, our understanding of the expression and functional role of the five SSTR subtypes in human (neuro-)endocrine tumors has increased significantly. The majority of human (neuro-)endocrine tumors express multiple SSTR. GH-secreting pituitary adenomas preferentially express SSTR2 and SSTR5, prolactinomas SSTR1 and SSTR5, and corticotroph adenomas express SSTR2 (low number) and predominantly SSTR5s. In addition, gastroenteropancreatic (GEP) neuroendocrine tumors frequently express multiple SSTR as well, with SSTR2 being expressed at the highest level. Treatment with the current generation of octapeptide somatostatin-analogs, e.g. octreotide and lanreotide, normalizes circulating GH- and IGF-I levels in approximately 60-70% of acromegalic patients, thereby remaining about one-third of patients uncontrolled. In patients with GEP neuroendocrine tumors, both somatostatin-analogs effectively suppress the production of bioactive peptides and hormones by the tumor cells, resulting in an important improvement of the related clinical symptomatology. However, a considerable proportion of patients experience an escape from treatment within months to several years. Altogether, the current generation of somatostatin analogs are effective medical tools in the treatment of acromegalic patients and of patients with neuroendocrine GEP tumors, but there is certainly a need for novel somatostatin analogs. In recent years, a significant number of novel somatostatin-ligands has been developed. These ligands include SSTR selective-, bi-specific, universal, as well as chimeric dopamine (DA)-somatostatin ligands. In vitro studies using human pituitary adenoma cells demonstrate a more profound inhibition of GH, PRL and ACTH secretion by somatostatin-analogs targeting both SSTR2s and SSTR5s, compared with SSTR2-preferential somatostatin-analogs. This likely reflects the SSTR subtype expression pattern in the adenoma cells. A first proof-of-concept trial with the more universal somatostatin-ligand SOM230 in 12 acromegalic patients shows that a single dose of SOM230 is effective in suppressing circulating GH concentrations in a significant larger number of patients compared with octreotide. In animal models, SOM230 has a better effect on GH and IGF-I level with less signs of tachyphylaxis compared with octreotide. Depending on the SSTR expression pattern on neuroendocrine GEP tumors, somatostatin-analogs targeting multiple SSTRs may play a future role in the more long-term control of patients with neuroendocrine GEP tumors. The first clinical trial comparing octreotide and SOM230 is ongoing. However, every advantage has its disadvantage. Targeting multiple SSTR potentially induces more adverse effects as well. Especially, glucose homeostasis might induce new problems in the long-term use of universal ligands.