In recent years, the number of approved targeted therapies for patients with advanced non-small-cell lung cancer (NSCLC) has steadily increased, making an efficient and effective molecular profiling of paramount importance in the management of NSCLC patients. To ensure that patients receive the most appropriate treatment, broad upfront molecular testing including both established and new targetable alterations should nowadays be routine practice in the diagnostic work-up of newly diagnosed patients with advanced NSCLC. Specifically for Belgium, ComPerMed guidelines recommend to test the mutational status of EGFR, KRAS and BRAF, screen for MET exon 14 skipping mutations and look for the presence of genetic fusions/rearrangements involving ALK, ROS1, RET, and NTRK1-3. These biomarkers should be analyzed in all patients with non-squamous NSCLC and in selected NSCLC patients with a squamous histology (i.e., never smokers, very young patients). Given the multitude of biomarkers that need to be tested, multigene testing using next generation sequencing (NGS) has gradually replaced sequential single gene testing as the preferred molecular screening tool in NSCLC. In fact, combined DNA/RNA NGS is now considered to be the most reliable and efficient approach for comprehensive detection of all approved and emerging biomarkers in advanced NSCLC (excluding PD-L1 detection). Both tissue samples as cytology specimens can be used for these NGS analyses as long as they contain a sufficient percentage of neoplastic cells and are processed in a way that safeguards nucleic acid integrity. In Belgium, a program is in place offering reimbursed DNA/RNA NGS testing to NSCLC patients through a network of 10 reference centers.