Pancreatic neuroendocrine tumors (pan-NETs) represent a highly heterogeneous and complex pathology, with therapeutic management and prognosis influenced by several biological and clinical characteristics. Chemotherapy, including regimens based on capecitabine and temozolomide (CAPTEM) or the combination of streptozotocin and 5-fluorouracil (STZ-5FU), is indicated for rapidly growing, symptomatic, or high-burden disease requiring swift cytoreduction. Historical studies provide scientific evidence for the STZ-5FU regimen, often retrospective and frequently analyzing small series. Despite these limitations, the efficacy of this treatment is well-established, and it is included in all guidelines as a therapeutic option. This systematic review aims to gather scientific evidence on using STZ-based chemotherapy to assess its real impact in managing well-differentiated metastatic or unresectable pan-NETs.