Pancreatic neuroendocrine tumors (pNETs) are rare and heterogenous tumors and surgery to remove theprimary tumor is the mainstay of treatment for resectable disease. However, curative surgery is often not feasible,because half of patients with pNET have metastases at the time of diagnosis. Palliative dubulking surgery andliver-directed therapies are appropriate options for these patients. Streptozocin-based regimens are standard,although temozolamide-based treatments are rapidly gaining wide clinical application. Somatostatin analogsare mainly indicated in hormonally active tumors to ameliorate symptoms. In addition, anti-tumoral activityhas been proven in well-differentiated NETs. Recently, there has been tremendous progress in the molecularbiology of pNETs; thereby, the efficacy of sunitinib and everolimus in the treatment of patients with metastaticpNETs has been proven by large placebo-controlled phase III trials. Currently, there are no definitively provenpredictive biomarkers to evaluate response to medical therapies in patients with pNET. Therefore, further studiesare needed to individualize and optimize their management. This article reviews systemic chemotherapy, targetedtherapies, and anti-secretory treatments for the management of patients with unresectable or metastatic pNETs,summarized in the light of recent advances.