Background: Identification of new drug targets may extend treatment options for neuroendocrine tumors (NET) regardless of histologic classification or primary organ site. Methods: 1,350 cases of infradiaphragmatic neuroendocrine tumors (all grades and sites) were identified among >60,000 cases profiled in a CLIA-certified laboratory. Biomarker profiling utilized multiple platforms: gene sequencing (next generation sequencing [NGS], Sanger or pyrosequencing), gene copy number (in-situhybridization), and protein expression (immunohistochemistry [IHC]). The results are shown relative to the total number of tests performed. Results: Overall, drug therapy-relevant alterations were identified in 1255 of 1350 (93%) of cases. Low or absent (0 or 1+ by IHC) expression of MGMT a biomarker of sensitivity to alkylating agents, was found in 149/243 pancreatic cases (61%), and in 488/1015 (48%) of non-pancreatic NET. Low or absent (0 or 1+ by IHC) expression of RRM1, a biomarker of gemcitabine sensitivity, was found in 927/1193 of NET (78%) and low or absent thymidine synthase, TS, a biomarker of fluoropyrimidines sensitivity, was shown for 950/1187 (80%) of NET by IHC. Sequencing of tumors showed oncogenic mutations in BRAF (6/446 (V600E in 4, and G596R in 2), CTNNB1 (3/223), KIT (4/357), EGFR (1/245), FGFR2 (2/224), GNAS (1/224), HRAS (2/192), PIK3CA (10/418), RB1 (4/222) VHL (2/203), KRAS (23/472), NRAS (2/349), and APC (14/224) and amplifications of EGFR (46/688) and MET (4/306. Therapies guided by mechanism-based biomarkers produced durable responses in documented cases: partial response (PR) >1 year to imatinib in a patient with KIT-mutant metastatic NET, and in cases of MGMT^low/TS^lowtreated with streptozocin or temozolomide plus fluoropyrimidine chemotherapy, thus supporting the clinical relevance of target profiling in NET. Conclusions: Comprehensive multiplatform profiling of a large series (n=1350) of NET, despite low frequency of individual biomarkers, identified clinically relevant targets in >90% of patients.Given the increasing utilization of chemotherapy for NET, our results provide the basis for future clinical trials to assess the efficacy of biomarker-based therapy for NET.