Superiority trials dominate the RCT landscape, asking whether a new treatment clearly outperforms placebo or standard care. Yet in many clinical contexts—where withholding proven therapy is unethical, or where novel options offer advantages like lower cost, fewer side effects, or easier delivery—non-inferiority and equivalence designs take center stage. These approaches are more nuanced, requiring careful definition of margins, appropriate active controls, and dual analyses (intention-to-treat and per-protocol) to avoid false conclusions. Non-inferiority trials test whether an intervention is not unacceptably worse than standard care, while equivalence trials demand evidence that outcomes fall within a tight range on both sides. Missteps in design or interpretation—such as unjustified margins, poor assay sensitivity, or inconsistent analyses—can undermine validity. Done rigorously, however, these designs expand treatment options and inform patient-centered choices, particularly when direct superiority is neither expected nor necessary.