Well-differentiated neuroendocrine tumors (NETs), which are also referred to as well-differentiated endocrine carcinoma according to WHO terminology, are usually slow-growing cancers, even when they exhibit gross local invasion and/or metastases. The survival of patients with metastatic NET is often measured in years to decades. Once NET progresses or becomes symptomatic the patient's prognosis is poor. An important challenge for clinicians is to distinguish at an early stage those patients who will die with the disease, from those who will succumb because of it, so that the appropriate level of care can be administered. Reliable genomic predictors could provide substantial advancements in prognosis and, possibly, treatment; however, such markers are currently unavailable. Early literature on the treatment of NETs is confounded by a lack of formal objective response criteria. Somatostatin analogs can control symptoms and can stabilize some slow-growing tumors, but rarely result in tumor regression. Surgery is curative in only a minority of patients, and systemic chemotherapy is minimally effective. Advances in the understanding of tumor biology have led to the identification of important cellular processes involved in the pathogenesis of NETs, and agents that target these processes have now entered clinical trials. We will discuss the data on therapies currently used to treat well-differentiated NETs, and the strategies being used in clinical trials.