Because of a surge in molecular testing capabilities concurrent with the rising numbers of targeted therapies in clinical development, the commercial use of predictive biomarkers before clinical validation is available is a topic of growing relevance to medical oncologists. Increasingly, patients will present questions about, requests for, and results from commercial biomarker tests for their oncologists to address. The sheer numbers of tests reaching the market, along with forecasted American Medical Association reforms in current procedural terminology coding and increasing FDA oversight of in vitro companion diagnostic device development, are likely to draw intense scrutiny to the regulation of commercial molecular testing in the near future, which will also require clinicians to remain abreast of the level of clinical validation of the biomarker tests available in practice. In addition to the direct risks of novel biomarker testing, including financial cost and ethical issues, the indirect risks encompass those associated with any clinical decision based on the biomarker test results. A great need exists for comprehensive and dynamic practice guidelines for all types of biomarker testing according to tumor type.