Current clinical practice guidelines recognize and as essential molecular biomarkers, and a host of other genetic alterations as emerging biomarkers for non-small cell lung carcinoma patients. The available approaches to detecting relevant alterations in these genes are diverse and often complementary. Laboratories have increasingly migrated away from a “single-gene test” approach, embracing assays that incorporate panels of genes capable of detecting a diverse set of alterations. The adoption of next generation sequencing (NGS) techniques has driven this shift; however, the approach to incorporation of NGS varies greatly between practices. Choice of molecular diagnostics assay, be it single-gene or NGS-based panel, will be driven by cost, urgency, clinical and laboratory focus, and professional considerations. Preanalytic factors including operator expertise, sample type and choice of fixative, and postanalytic factors including informatics pipeline and approaches to variant reporting have a significant impact on the quality of molecular diagnostics results. There is no real “one-size-fits-all” test for genomic profiling for lung cancer; clinicians and laboratorians must be prepared to offer a diverse set of assays in order to address turnaround time requirements and optimize detection of critical but difficult-to-detect tumor alterations such as gene fusions.Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.