Background: ATC is the most aggressive type of thyroid cancer with a median survival of 5 months from diagnosis. ATC patients with genomic alterations (GA) in TSC2, ALK, BRAF show occasional, limited benefit with targeted therapies. Methods: 90 ATC were studied by CGP to define the frequency of GA and opportunities for targeted therapy approaches in this devastating disease. DNA was extracted from 40 microns of FFPE sections, and CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 579X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. GA included base substitutions, indels, amplifications, copy number alterations and fusions/rearrangements. R software used for all statistical analyses. Fisher’s exact test used for mutation frequency comparisons among age groups. Results: Median patient age was 65 (range 33-86), 50 patients were male. There was a mean of 4.2 Known Likely Variant (KLV) genomic alterations per case, range 1-11. Adding Variants of Undetermined Significance (VUS) mean was 12.9, range 5-27. The most common KLV-GA were p53 (66%), BRAF (34%), TERT (32%), CDKN2A (32%), NRAS (26%), CDKN2B (20%), NF2 (14.4%), PTEN (13.3%), PIK3CA (12.2%). There were 2 EGFR; 5 JAK2 and 29 GAin the promoter region of TERT. BRAF V600E and NRAS/HRAS alteration were entirely mutually exclusive, and one case demonstrated both BRAF V600E and KRAS. Co-occuring mutations were CDKN2A with p53 (p=0.04). Some GA were more frequent in patients greater than ≥70 yrs of age such as BRAF, CDKN2A, PIK3CA, JAK2; while others were more common in ≤50 yrs patients like PTEN, NRAS. VUS of possible interest were MLL2 (n=15), ARID1A (11), TSC2 (5), ALK(2). Conclusions: A number of identified alterations in ATC patients may be amenable to molecularly targeted therapies, guiding future clinical trial development. Further assessment will be performed to the relationship of GA in ATC with patient demographics and disease evolution from differentiated thyroid carcinoma.