Important progress has been made during the last decade in the histopathologic characterization and overall prognostic evaluation of gut neuroendocrine tumors. However, some issues like tumor histogenesis, typing, functional characterization, and preferred site of origin deserve further clarification. This is a survey of the present status of the matter outlining some of the open points. In particular, careful comparison of normal gut endocrine cell types with related endocrine tumors so far identified shows an unexplained lack of neoplasms involving upper small intestine cells like secretin, cholecystokinin, motilin, and GIP cells, as well as the equally unexplained concentration of serotonin EC cell tumors in the ileum and appendix or of somatostatin cell tumors in the duodenal papillary region, despite their wide distribution in the normal gut, not to mention gastrinomas arising in the pancreas, normally devoid of gastrin cells. Special functional (e.g., achlorhydria-driven hypergastrinemia) or pathologic (as chronic inflammation) conditions may locally influence the proliferative and differentiation state of the endocrine cells thus promoting tumor growth. Tumor histologic structure, differentiation level, and proliferative index as well as gastrointestinal wall barriers to tumor diffusion may account for most prognostic parameters, with considerable changes, however, according to the tumor type and site. Thus, further work is needed to develop tumor- and site-adjusted prognostic parameters.