Background: NSGCT, the most common solid malignancy in U.S. men ages 18-35, has a > 95% 5-year survival due to exquisite chemosensitivity; however, chemoresistant recurrences still contribute to 400 NSGCT deaths/year. We queried CGP results of the largest collection to date of recurrent NSGCT (n = 28) to identify targeted therapy options for this subset of high risk patients. Methods: DNA was extracted from 28 FFPE NSGCT clinical specimens. Hybridization captured libraries of 236 (FoundationOne, n = 20) or 305 (FoundationOne, n = 8) genes, plus select introns frequently rearranged in cancer were sequenced to high ( > 605x), uniform coverage. All classes of genomic alterations (GA; base subs, in/dels, rearrangements, and copy number alterations) were evaluated. CRGA were defined as GA associated with on-label targeted therapies and targeted therapies in mechanism-driven clinical trials. CGP coverage data was used to assess for chromosome 12p arm amplifications. Results: 28 samples (29% primary, 71% metastasis) from patients (avg 33.7 y) with recurrent NSGCT of predominant pattern of yolk sac tumor (43%), embryonal carcinoma (18%), choriocarcinoma (18%), or unspecified/mixed (21%) were profiled. 57% of NSGCT had chromosome 12p amplification ( > 6 copies). 89% had at least one GA not localized to chromosome 12p, including CRGA of CRKL (11%), MCL1 (11%), MDM2 (11%), GNAS (11%), KRAS (SV 7%), AURKA (7%), KIT (7%). CRGA in each of: AKT1, AKT2, BRAF, ERBB2, NF1, PIK3R2, PDGFRA, STK11 were identified in a single case. To date, we are aware of one patient in whom treatment with everolimus was initiated on the basis of the CGP results (inactivating point mutations in STK11 and PIK3R2) and who experienced marker stabilization lasting 5 months suggesting a biologic effect of this therapy. Conclusions: GA not accounted for by 12p amplification are present at a higher frequency than previously reported in recurrent or treatment-resistant NSGCT. The prevalence of CRGA and clinical response to targeted therapy in one such patient support the utility of CGP to identify additional therapeutic options for high risk NSGCT and warrants additional study.