Pancreatic neuroendocrine neoplasms (pNENs) are rare cancers with broad challenges for their management. Themain clinical obstacles are the high rate of patients diagnosed at advanced stages, lack of prognostic markers forearly detection of disease recurrence in resected patients, significant limitations in identifying those who willbenefit from adjuvant therapy, and timely recognition of treatment response. Therefore, the discovery of newprognostic and predictive markers is necessary for patient stratification and clinical management. Liquid biopsy,which has revolutionized the field of clinical oncology, is extremely under-investigated in pNENs. This reviewhighlights its potential and the recent advances in related technologies, as candidates for the delivery of the newtools that can help to refine pNEN diagnosis and to personalize treatment. In addition, the opportunities andlimitations of available preclinical research models with regard to biomarker research are discussed in light ofpNEN clinical needs.