Neuroendocrine neoplasms (NENs) are characteristically heterogeneous tumors, with a great variability in symptomatology and clinical course, making their management challenging for physicians. The adequate therapeutic approach relies on the correct diagnosis and staging by means of accurate pathology classification, wise utilization of radiological and biomarker tests, and thorough clinical evaluation of NEN-associated hormonal syndromes. In this chapter, we discuss the general and anatomical site-specific components of the initial workup of patients with NENs, including pathological diagnosis, the recommendation for conventional and functional imaging tests, the utility of biochemical markers, and the characteristics of NEN-associated hormonal syndromes. We also present the basic concepts of the initial workup of very early stage NENs, G3 NENs, carcinoid syndrome, and genetic syndromes with high risk of NENs. These aspects are essential to understand tumor biology, inform prognosis, and determine tailored treatment decisions.