Background: NENs can occur in many locations but have limited precision therapy options. DLL3 is a cell surface protein that is emerging as a promising therapeutic target in NENs including neuroendocrine prostate cancer (NEPC) and small cell lung cancer (SCLC). Our recent study indicated that ̃77% of NEPCs expressed DLL3, with expression in circulating tumor cells being highly concordant with matched biopsies. While there are ongoing clinical trials of drugs targeting DLL3, the repertoire of clinical and genomic features shared across other DLL3-expressing NEN cancers is ill-defined. Methods: We analyzed WES and WTS data from NENs identified across 29 different sites of origin using the Caris Life Sciences platform, excluding SCLC and including neuroendocrine carcinomas and neuroendocrine tumors. We used values above or below median DLL3 expression of all NEN samples to define DDL3-High/Low (H/L). Significance of molecular alterations in DLL3-H vs L was determined using Fisher’s-Exact/Mann Whitney/X² test with Benjamini-Hochberg correction. Results: DLL3 expression across all 2672 NEN samples was observed in 27 of 29 NENs after excluding SCLC. NENs of anus, prostate, lung, bladder, and bile duct exhibited the greatest median DLL3 expression, whereas adrenal gland, small bowel, and nervous system displayed the lowest. Certain tissues of origin displayed more robust DLL3 expression, with 71% (50/66) of NEPC, 75% (87/122) of lung, and 77.3% (51/66) of bladder being DLL3-H compared to 14.4% (13/90) of adrenal and 7.9% (12/151) of small bowel NENs. DLL3-H NENs were associated with TMB-high status ( > 10 muts/Mb; 12.1% vs 4.5%, OR 2.7, q < 0.001) and more genomic alterations in several driver genes, including tumor suppressors TP53 (51% vs 23%, OR 2.3, q < 0.001) and RB1 (42% vs 10%, OR 4.2, q < 0.001), and oncogenes KRAS (14% vs 5.4%, OR 2.5, q < 0.001), MYC (5.7% vs 0.9%, OR 6.3, q < 0.001) and CCNE1 (5.3% vs 1.3%, OR 4.0, q = 0.001). Conversely, DLL3-L NENs exhibited more alterations in CTNNB1 (2.2% vs 5.2%, OR 0.42, q = 0.04), MEN1 (3.3% vs 11%, OR 0.30, q < 0.001), and BCOR (1.3% vs 4.1%, OR 0.32, q = 0.02). DLL3-H NENs also had significantly more alterations in PIK3CA (6.4% vs 3.0%, OR 2.1, q = 0.04), chromatin remodeling genes KMT2D (6.7% vs 2.6% OR 2.6, q = 0.005) and CREBBP (3.2% vs 0.9%, OR 3.6, q = 0.03), and WNT signaling gene APC (9.7% vs 5.2%, OR 1.9, q = 0.02). Conclusions: We confirmed DLL3 expression in NENs across different tissues of origin, with highest expression in poorly differentiated NENs. DLL3-H expression was associated with genomic features considered “undruggable” based on current precision therapy approaches. Therefore, DLL3-targeted therapies may serve as a promising strategy for NEN patients with functional loss of tumor suppressors TP53 and RB1, as well as increased activity of KRAS, WNT and MYC signaling.