Acromegaly is mainly due to the somatotroph pituitary neuroendocrine tumors (PitNET)s. These have been subtyped into densely granulated (DG) and sparsely granulated (SG) tumors, which differ in clinical, histological and biological characteristics and in response to somatostatin analogs (SA)s. The variable remission rate after surgical resection, as first line treatment, has increased interest in identifying pathological markers to better predict the response to medical treatment. Several techniques have shown somatotroph tumors to express somatostatin receptors (SSTR)s, and mainly SSTR2 and SSTR5. The molecular methods appear to give contradictory results, are expansive and cannot be routinely performed. Immunohistochemistry, while being the most powerful technique, requires optimal fixation and the use of monoclonal antibodies against at least SSTR2 and SSTR5. Almost all somatotroph tumors express SSTR2 or SSTR5, and, in great majority, at a high level. More importantly, the type of SSTR, the level of expression, and the response to SA treatment appear well correlated. Indeed, a significantly higher expression of SSTR2 in DG compared to in SG tumors likely explains the better response of DG tumors to the normalization of growth hormone and insulin-like growth factor-1 under SA. However, a reproducible scoring and a cut-off from which the SA efficacy can be reliably predicted, remain to be found. In conclusion, the SSTR expression profile and morphological subtypes of the somatotroph tumor may help predict the response to medical treatment. Such pathological profiling could become a useful decision-making tool for clinicians in the context of a multidisciplinary approach, after surgery failure.