Over the last decade, the treatment of patients with advanced non-small cell lung cancer (NSCLC) has become reliant on tissue and/or blood biomarkers to help guide treatment decisions. There are now multiple biomarker-defined patient subgroups, with evidence showing that treatment with targeted therapies has superior clinical outcomes when compared with traditional cytotoxic chemotherapy. However, rapid change in the field of precision oncology brings with it the challenge of translating recommendations into clinical practice. In this review, we discuss the major guidelines recommending biomarker testing in NSCLC, as well the logistical challenges to applying these guidelines to patients with NSCLC both in the United States and worldwide. The techniques commonly used for biomarker testing will be discussed, both for tissue- and blood-based biomarkers. Finally, we discuss the challenge of interpreting the results of biomarker testing and using these results to guide treatment decisions.