Peptide receptor radionuclide therapy (PRRT) represents an innovative and effective treatment option for well-differentiated neuroendocrine tumors (NET). Although first employed in mid-1990s as part of clinical trials, the only currently approved radiopharmaceutical is [177Lu]Lu-DOTATATE (EMA, 2017; FDA, 2018). Patients’ indication to PRRT is generally discussed at multidisciplinary level to evaluate both patients’ eligibility and the individual risks/benefits. In Europe, PRRT with [177Lu]Lu-DOTATATE is EMA-approved for treatment of unresectable or metastatic, progressive, well-differentiated (G1–G2), somatostatin receptor (SST)-positive gastro-entero-pancreatic NET in adults, while in the USA approval is extended to children >12 years old and the NCCN guidelines also considers PRRT in well-differentiated lung NET and in pheochromocytomas and paragangliomas. Overall, PRRT is associated with a significant improvement in survival, is well tolerated, and improves patients’ quality of life. The optimal strategy for assessing response to PRRT is still under study, clinically is generally performed using a combination of morphological and functional imaging. Many efforts are focused to optimize treatment personalization and to assess the most appropriate positioning of PRRT in the treatment sequence.