Background: Prostate cancer is the second leading cause of cancer-related death among men in the U.S. Forty percent of men diagnosed will develop metastatic disease, which has few treatment options. We aim to describe the molecular profile of prostate cancer tumors and potential for novel therapeutic options. Methods: We reviewed profiling data of over 330 patients from a large referral laboratory (Caris Life Sciences, Phoenix, AZ) for biomarkers of drug response. Multiple methodologies were employed: sequencing (NGS, Sanger, pyrosequencing), in-situ hybridization (fluorescent and chromogenic), and immunohistochemistry. Results: High expression was observed for AR, MRP1, TOPO1, TLE3 and EGFR, with positivity rates of 89%, 87%, 63%, 48%, and 47%, respectively. Low expression was observed for TS, PGP, TUBB3, RRM1, PTEN and MGMT, with negativity rates of 94%, 87%, 75%, 69%, 54%, and 45%, respectively. Gene copy number increases for EGFR and cMYC were observed in 13% of patients. Sequencing data showed a 48% mutation rate for TP53, 18% for PTEN, 9% for CTNNB1, 8% for PIK3CA, 5% for RB1, ATM, and cMET, and approximately 2% for K/HRAS, ERBB4, ALK, BRAF, and cKIT. Targeted therapy options include imatinib for patients with high cKIT or PDGFRA (9 to 10%) and cetuximab for patients with EGFR positivity (13 to 47%). Promising agents may be considered, including cabozantinib, based on 4% of cohort with cMET aberrations or PAM pathway inhibitors (BEZ234, everolimus) based on approximately 30% of cohort with PIK3CA pathway activation. Lastly, HDAC inhibitors have recently been linked to cMYC driven cancers (13% amplified). 5-FU, gemcitabine, and temozolomide chemotherapies may be options, as approximately 70% of cohort with low TS, RRM1, or MGMT. Biomarker guidance for common prostate cancer drugs such as cabazitaxel is also provided, based on approximately 70% of cohort with low TUBB3 or PGP, or high TLE3. Also, continued dependence on androgen signaling is exhibited by 89% of cohort with high AR, indicating potential utility of anti-androgen agents like enzalutamide. Conclusions: Tumor profiling identified small subsets of patients that may benefit from targeted agents approved for other solid tumors (imatinib, cetuximab), promising therapies in clinical trials (cabozantinib) or agents not routinely used for prostate cancer (gemcitabine).