Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) constitute a heterogeneous group of tumours associated with variable clinical presentations, growth rates, and prognoses. To improve the management of GEP-NENs, the WHO developed a classification system that enables tumours to be graded based on markers of cell proliferation in biopsy specimens. Indeed, histopathology has been a mainstay in the diagnosis of GEP-NENs, and the WHO grading system facilitates therapeutic decision-making; however, considerable intratumoural heterogeneity, predominantly comprising regional variations in proliferation rates, complicates the evaluation of tumour biology. The use of molecular imaging modalities to delineate the most-aggressive cell populations is becoming more widespread. In addition, molecular profiling is increasingly undertaken in the clinical setting, and genomic studies have revealed a number of chromosomal alterations in GEP-NENs, although the 'drivers' of neoplastic development have not been identified. Thus, our molecular understanding of GEP-NENs remains insufficient to inform on patient prognosis or selection for treatments, and the WHO classification continues to form the basis for management of this disease. Nevertheless, our increasing understanding of the molecular genetics and biology of GEP-NENs has begun to expose flaws in the WHO classification. We describe the current understanding of the molecular characteristics of GEP-NENs, and discuss how advances in molecular profiling measurements, including assays of circulating mRNAs, are likely to influence the management of these tumours.