Non–small cell lung cancer (NSCLC) has become a prominent example of precision medicine among solid tumor malignancies. Clinical management of NSCLC now depends on surgical, chemotherapeutic, and radiation treatment regimens based on pathologic findings and clinical staging as well as targeted therapies based on molecular profiling. As molecular testing becomes increasingly important, preserving tissue for this purpose while rendering an accurate histological diagnosis becomes a key consideration, particularly in advanced-stage NSCLC, in which small biopsy samples or aspirates are often the only specimen available. Next-generation sequencing panels are a powerful method of providing information relevant for both standard-of-care and investigational treatment options. However, taking advantage of the abundance of information gleaned from these panels requires careful annotation, prioritization, and reporting of molecular findings and their clinical significance. Although molecular profiling has traditionally relied on direct sampling of neoplastic tissue, blood-based diagnostics now offer the potential to provide some clinically useful information noninvasively.