Rarely is it straightforward to specify the design and parameters of a clinical trial investigating an alternative therapy where effective therapies already exist. If existing therapeutic interventions are highly efficacious, safe, inexpensive, and firmly entrenched, an active-control design becomes the logical first choice. Short of this absolute condition, however, the merits and realities of the scientific, clinical, corporate, and regulatory environments need to be weighed before determining the appropriate approach. A state of clinical equipoise with regard to the use of glycoprotein (GP) IIb/IIIa therapy in percutaneous coronary intervention (PCI) provided the unique opportunity to address the complexities in selecting a placebo-controlled design for the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Trial (ESPRIT). ESPRIT investigators assessed whether a high dose of eptifibatide would improve the outcomes of patients undergoing coronary stenting. By using the example of the ESPRIT trial, we examine factors warranting the need for this trial and evaluate the process whereby the United States Food and Drug Administration (FDA) gave approval for a placebo-controlled design. Although the focus of this trial is GP IIb/IIIa inhibition therapy, the issues pertaining to the trial and how they were resolved are general enough to be applied to the design and conduct of clinical trials across a broad spectrum of illnesses and therapeutic modalities.