Simple SummaryPrecision medicine has reached its current peak in non-small cell lung cancer (NSCLC), with a constantly growing number of predictive biomarkers and new targeted therapies that when applied, significantly affect and change outcomes. Hence, the matter in question is how we might optimally detect and implement them in the treatment of our patients in everyday clinical practice. The main problem in the diagnostic workup of NSCLC is the rather limited tumor sample used on many occasions in the classical diagnostic approach, which consists of a series of single-biomarker tests. Consequently, the introduction of comprehensive genomic profiling (CGP) in everyday diagnostic and clinical practice is one of the imperatives that could benefit everybody involved. Here, we present national data and our experiences with the application of comprehensive genomic profiling in NSCLC. The results have shown the utility and potential benefit of comprehensive genomic profiling, but also challenges involved in the implementation of precision oncology in clinical practice. So when possible, CGP should be used as an upfront backbone diagnostic and treatment-oriented work-up in patients with NSCLC.AbstractNon–small cell lung cancer (NSCLC) has become the best example of precision oncology’s impact on outcomes in everyday clinical practice, significantly changing the expectations of all stakeholders, including medical professionals, society, and most importantly, patients. Consequently, the implementation of the precision oncology concept in medical systems, in order to achieve optimal and proven curative effects in NSCLC, is imperative. In this study, we investigated the development, challenges, and results associated with the implementation of precision oncology in NSCLC on a national level in Croatia. We conducted a multicenter, retrospective, cross-sectional analysis on the total population of Croatian patients with metastatic lung cancer, on whose tumors specimen comprehensive genomic profiling (CGP) testing was performed during 2020 and 2021. A total of 48 patients were included in the study. CGP revealed clinically relevant genomic alterations (CRGA) in 37 patients (79%), with a median of 2 (IQR 1–3) CRGA per patient. From the panel of recommended tests,KRAS,MET, andEGFRwere the most common alterations, detected in 16 (34%), 5 (11%), and 3 (6%) patients, respectively. CGP revealed additional targetable mutations in 29 (60%) patients who would not have been tested (and consequently, whose mutations would not have been detected) according to the existing everyday standard of practice in Croatia. The tumor mutational burden was reported as high (≥10 Muts/Mb) in 19 patients (40%). CGP analysis reported some kind of targeted therapy for 34 patients (72%). CGP revealed other potentially targetable mutations, and it also determined TMB to be high in a significant number of patients. In conclusion, when possible, CGP should be used as an upfront backbone diagnostic and treatment-oriented work-up in patients with NSCLC.