This chapter reviews systemic therapy for metastatic gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), encompassing cytotoxic chemotherapy, targeted therapies, peptide receptor radionuclide therapy (PRRT), somatostatin analogs (SSA), and immunotherapy. Treatment choice is guided by tumor grade, differentiation, somatostatin receptor (SSTR) expression, and clinical aggressiveness. SSA are established as first-line therapy in well-differentiated (G1/G2) neuroendocrine tumors (NETs), offering both symptom control and antiproliferative benefit. For progressive disease, targeted agents such as everolimus, sunitinib, and cabozantinib improve progression-free survival, particularly in pancreatic and nonpancreatic NETs. PRRT with ^177Lu-DOTATATE provides durable disease control in SSTR-positive tumors, with phase III data supporting use in midgut NETs and ongoing studies expanding its role to higher-grade disease. Cytotoxic chemotherapy remains a key strategy for poorly differentiated NECs, high-grade NETs, and pancreatic primaries, with regimens such as capecitabine/temozolomide (CAPTEM), streptozocin-based combinations, and platinum-based therapies demonstrating efficacy in selected subgroups; biomarkers such as MGMT deficiency refine patient selection. Immunotherapy has shown limited activity in well-differentiated NETs but holds promise in NECs, where higher tumor mutational burden and PD-L1 expression suggest greater immunogenicity. Although monotherapy yields modest outcomes, combination regimens and novel immune-based strategies are under active investigation. Overall, systemic therapy for metastatic GEP-NENs has become increasingly multimodal, with rational sequencing of SSA, targeted agents, PRRT, chemotherapy, and emerging immunotherapy guided by tumor biology and clinical context.