Neuroendocrine neoplasms (NEN) are a class of tumours heterogeneous in terms of their anatomical sites of origin and clinical behaviour. Outdated perspectives of indolence have been superseded by appreciation for their myriad clinical challenges, such as the high rates of regional and distant metastases at initial diagnosis, lack of clarity on optimal treatment strategies/sequencing, and incompletely elucidated genetic/other pathophysiological drivers. The first randomised controlled trials in this arena were published approximately a decade ago – since then, increased understanding of the genetic drivers and signalling pathway perturbations in these tumours have suggested promise for precision therapy influenced by an individual tumour’s molecular sub-type, but this is yet to be realised for manifold reasons. In this article, the authors review the genetic landscapes as currently understood for selected forms of NEN and discuss the current and developing evidence to support the use of genetic information to influence therapy. They provide a critical assessment of the potential limitations of using such approaches and also posit avenues for future developments in this arena.