The natural history of patients with neuroendocrine neoplasms (NENs) is characterized by pronounced interpatient heterogeneity. This clinical variability reflects the diverse biology of NENs that show a wide spectrum of cell differentiation, proliferation, and invasiveness. A major determinant of the clinical course is attributed to the increased production and secretion of a multitude of neuropeptides and amines that cause distinct clinical syndromes. Over-secretion of a single hormone (functioning tumor) or absence of any hormonal over-secretion (non-functioning tumor) are the two most common clinical scenarios observed in NENs patients with sporadic disease. However, concomitant secretion of multiple peptides at diagnosis can be observed in patients with multiple endocrine neoplasia syndromes and is attributed to the coexistence of tumors of separate origins. The concurrent secretion of multiple hormones at diagnosis as well as the development of secondary hormone secretion have been described to occur in a minority (9.3%) of sporadic NENs patients, mainly of pancreatic origin, in the presence of metastatic disease. Secondary hormone secretion was associated with disease progression as well as with increased morbidity and mortality. Patients with metastatic NENs should be closely monitored for the appearance of clinical symptoms of secondary hormone secretion during the disease course; a timely diagnosis requiring a high index of suspicion is major in order to improve the outcomes of these patients. The molecular basis underlying production and secretion of different hormones in NENs is poorly studied, though hormonal plasticity and reprogramming of the hormone secretion have been shown to occur both spontaneously or during experimental manipulation.