Aims: The hierarchy of evidence-based medicine determines the inferential powers of different clinical research designs. We want to address the difficult question if observational evidence under some circumstances can validate intervention effects. Methodology: Assessment of previous argumentation aiming at a clear conclusion for future decision-making. Results: We present five arguments demonstrating the fundamental need of randomized clinical trials to sufficiently validate intervention effects. Furthermore, we argue that hindrances to the conduct of randomized clinical trials can be lessened through education, collaboration, infrastructure, and other measures. Our arguments validate why the randomized clinical trial should and must be the study design evaluating interventions. By choosing the randomized clinical trial as the primary study design, effective preventive, prognostic, diagnostic, and therapeutic interventions will reach more patients earlier. Conclusion: Clinical experience or observational studies should never be used as the sole basis for assessment of intervention effects-randomized clinical trials are always needed. Therefore, always randomize the first patient as Thomas C Chalmers suggested in 1977. Observational studies should primarily be used for quality control after treatments are included in clinical practice.