<p>Pancreatic neuroendocrine neoplasms (pNENs) are a highly heterogeneous group of tumors, encompassing well-differentiated neoplasms with relatively indolent clinical behavior and poorly differentiated carcinomas with aggressive disease courses. In clinical practice, treatment decisions must be individualized, integrating tumor grade, differentiation, molecular profile, and the dynamic evolution of disease. For well-differentiated tumors with somatostatin receptor positivity, we favor somatostatin analogs or peptide receptor radionuclide therapy as first-line options, followed by molecularly targeted therapies such as mTOR inhibitors and anti-angiogenic agents upon disease progression. Chemotherapy remains indispensable for patients with high proliferation indices or rapidly progressive disease. For poorly differentiated carcinomas, platinum-based regimens remain the backbone of systemic therapy, though outcomes are limited. Emerging strategies—including targeted therapies, immune checkpoint inhibitors, and rational combinations—are showing promise in selected patients, particularly those with actionable molecular alterations such as DNA mismatch repair deficiency. In the absence of a defined therapeutic sequence, our approach emphasizes molecular profiling, multidisciplinary collaboration, and dynamic adaptation of treatment strategies, while carefully incorporating patient preferences, to achieve durable disease control. Ultimately, building an individualized framework grounded in precision medicine is key to improving both survival and quality of life for patients with pNENs.</p>