The fascinating, but often unpredictable, biology of neuroendocrine tumors (NETs) make the management of these malignancies a real challenge. The more recent development of high-throughput genomic and proteomic techniques, have opened a window to an increased knowledge of the biology of NETs. This review will discuss genes thought to play a role in the context of NE tumor biology, with particularly attention to those that may be potential new diagnostic and prognostic markers, as well as therapeutic targets. NETs constitute a heterogeneous group of neoplasm that may arise in virtually every topographic localization in the body, as a consequence of malignant transformation of various types of NE cells. Since NETs arising in the gastroenteropancreatic (GEP) or bronchopulmonary system are by far the most common, this review focuses on these entities, but lines are drawn to other NETs as well. Although large-scale gene expression analysis undoubtly have raised interesting new hypothesis concerning genes thought to play a role in tumor biology, discrepancies observed between studies and various platforms used, emphasizes the need to not only standardize the way microarray data are reported, but also to introduce standards in sample taking, processing and study design. In addition, the recognition of the complexity of the human proteome, with regard to generation of multiple isoforms from one gene, has created additional challenges. However,some goals have been reached already, as new knowledge has been translated into development of novel promising therapeutics.