Background: Advances in tumor genomic profiling offer the promise of precision oncology but a systematic prospective evaluation is lacking. We conducted a prospective cohort study of tumor genomic testing to identify prevalence of actionable alterations and their impact on management decisions. Methods: Patients provided written informed consent for this prospective cohort study approved by the Cleveland Clinic Institutional Review Board. Eligibility requirements included pathologic diagnosis of select solid tumor malignancies without a known curative option, age ≥ 18 years, and ECOG PS 0-2. Tumor samples were sequenced for up to 315 candidate genes using FoundationOne (Cambridge, MA). Results were reviewed at the Cleveland Clinic Genomics Tumor Board (GTB) for biologically actionable alterations, defined as those linked to an approved therapy in the solid tumor under study or another solid tumor, a clinical trial, or a contraindication to a targeted therapy. Sample size was 250 patients. Outcomes were feasibility and clinical impact of tumor sequencing. Results: From Aug 2013 to Oct 2014, all 250 patients were enrolled. Median age was 60 years; 128 (51%) were female; 220 (88%) were white. Colorectal (25%), breast (18%), lung (13%), pancreatobiliary (12%), and head and neck (10%) cancers were common diagnoses. Median time from consent to genomic test result was 25 days (range, 3-140), with 27 (11%) samples having insufficient tissue for analysis. Of 223 resulted samples, an alteration was found in 96% (n = 214), with a median of 4 (0-20) alterations per sample. At GTB review, a biologically actionable alteration was declared in 63% (n = 141) of cases. However, only 10% (n = 22) of patients received tumor genomics-driven targeted therapies: 12 went on clinical trials, 3 received on-label drugs, and 7 received off-label drugs. Lack of clinical trial access was the most common reason for non-recommendation/receipt of genomics-driven therapy. Conclusions: This prospective study shows that routine tumor genomic profiling is feasible, with almost two-thirds of resulted samples having a biologically actionable alteration, but paucity of genomics-driven clinical trials of targeted therapies is a barrier to the success of precision oncology.