Biomarker-directed precision medicine has revolutionized the management of lung cancer, particularly non-small cell lung cancer (NSCLC), by enabling personalized treatment approaches that improve both survival and quality of life. This chapter outlines the critical role of biomarkers in guiding targeted therapies and immunotherapies, emphasizing their impact on therapeutic decision-making, minimizing toxicity, and maximizing efficacy. Comprehensive biomarker testing, including DNA and RNA-based next-generation sequencing (NGS), immunohistochemistry (IHC), and liquid biopsy, has become essential in identifying actionable molecular alterations and optimizing treatment sequencing. The chapter explores practical considerations in biomarker testing, including biospecimen acquisition, preanalytical requirements, and test modalities, while highlighting challenges such as limited tissue availability and the need for rapid turnaround times. It stresses the importance of timely and sequential testing at diagnosis and relapse, especially for detecting resistance mechanisms. A multidisciplinary approach involving oncologists, pathologists, and allied healthcare professionals like nurse navigators is critical to streamlining testing workflows and ensuring timely initiation of precision therapies. Key biomarkers, such as EGFR mutations, ALK rearrangements, and PD-L1 expression, are discussed alongside their associated therapies. The chapter concludes by emphasizing the transformative potential of biomarker-guided treatment in improving outcomes and paving the way for future advances in lung cancer care.