Somatostatin agonists (SM-As) are capable of achieving durable symptomatic relief and significant clinical responses in certain tumours. Herein, we review the diverse direct and indirect mechanisms of antineoplastic activity elicited by SM-As as well as the hurdles that complicate their use as monotherapies in a broader range of malignancies. Emphasis is placed on recent clinical attempts to neutralise the IGF-mediated survival factor effects in the bone metastasis microenvironment in advanced prostate cancer. The first clinical trials of this 'anti-survival factor manipulation' strategy utilised the ability of SM-As to suppress the growth hormone-dependent liver-derived IGF-I bioavailability in combination with other drugs, such as dexamethasone, zolendronate and oestrogens, acting systemically and at the bone metastasis microenvironment. These regimens restored androgen ablation responsiveness in stage D3 prostate cancer patients and successfully produced objective clinical responses while only mild toxicities were observed. Furthermore, we focus on the preclinical experimental data of a targeted SM-A coupled to the super-potent doxorubicin derivative AN-201. The resulting conjugate (AN-238) has shown increased antitumour potency with a favourable toxicity profile. The potential use of novel SM-As as anticancer drugs is discussed in relation to data suggesting other direct and indirect treatment approaches pertaining to the somatostatin system.