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The management of neuroendocrine neoplasms (NENs) remains a perplexing problem due to the lack of knowledge of the biology of the disease, its late presentation, the relative insensitivity of imaging modalities, and a critical limitation posed by the lack of accurate biomarkers to guide management and monitor the efficacy of therapy. Current clinical practice involves the mutual consideration of both imaging and biomarkers. Simple monoanalyte measurements, however, often do not correlate with radiological evaluation. The NETest multigene measurement is a highly sensitive, clinically validated diagnostic tool that allows rapid detection of tumor-related genes, in a reproducible, cost-effective, and standardized model. Circulating NET genes can be identified in as few as one tumor cell/milliliter. Published data identify the value of transcriptomic analysis in the diagnostic and monitoring setting of a variety of therapeutic modalities, particularly in conjunction with other clinical and imaging parameters to monitor disease progression. We predict that future strategies for refining and improving the evaluation of therapy will be provided by incorporating imaging modalities and the blood-based molecular information provided by tumor transcriptomic analysis. One such example is provided by circulating RNA-based peptide receptor radionuclide therapy (PRRT)-predictive signature. A predictor strategy is of importance not only for forecasting drug efficacy but also for identifying potential drug toxicity. The identification of transcript profiles for the blood or kidney that can monitor such emerging risks or predict them is an important developmental goal for neuroendocrine tumor (NET) liquid biopsies.