Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms that originate from neuroendocrine stem cells and express both neural and endocrine markers. They are found in almost every organ, and while NENs are mostly associated with slow growth, complications due to the uncontrolled secretion of active peptides, and metastatic disease, may significantly impair the quality of life and can ultimately lead to the death of affected individuals. Expanding knowledge of the genetic, epigenetic, and proteomic landscapes of NENs has led to a better understanding of their molecular pathology and consequently increased treatment options for patients. Here, we review the principal breakthroughs in NEN treatment management, owing largely to omics technologies over the last few years, current recommendations of systemic treatment, and ongoing research into the identification of predictive and response biomarkers based on molecular targeted therapies.