Background: In GBM, molecular markers are utilized to establish an integrated diagnosis as described in the WHO 2016 guidelines and identify patients (pts) with molecular targets amenable to therapeutic intervention. Herein we review our experience at Moffitt Cancer Center. Methods: A retrospective chart review between 4/1/2013 and 11/1/2018 was performed to collect demographic, clinical, disease, treatment and outcome variables on 163 unique pts with GBM whose tumors underwent comprehensive genomic profiling by FoundationOne or CDx testing. Genomic data was analyzed for recurrent alterations and tumor mutational burden (TMB). Results: Median age was 58 years (range 19 to 85). 13% were IDH1 or 2-mutated. Among the 141 IDH-wild type (wt) pts, TERT promoter mutations occurred in 83% and CDKN2A/B co-deletion in 65%. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was seen in 33%. A median of 5 clinically relevant alterations were identified per tumor sample (range, 2 to 34) and a median of 2 mutations (range, 0 to 6) were found to be actionable after review by our molecular tumor board. The most commonly actionable alterations were found in EGFR, BRAF and genes associated with homologous recombination deficiency (HRD) (see table). Four pts were treated with EGFR-targeted therapy, one pt with an HRD alteration received a PARP inhibitor (progression free survival [PFS] of 34 weeks), and two pts with BRAF V600E received dabrafenib/trametinib combination therapy (treatment ongoing at 14 weeks and 38 months, respectively). Median TMB (n = 118) was 4 (range, 0 to 371 Muts/Mb). One pt who received 44 months of temozolomide exposure had a hypermutated tumor (371 Muts/Mb) and was treated on trial with pembrolizumab, but progressed after 2 months. Conclusions: Though limited in patients with GBM, clinically actionable alterations are found in a small subset and can translate into meaningful clinical benefit.