There is perhaps no more important time to consider the history of placebos and their role in clinical trials and in medicine. Increasingly, well-designed pharmaceutical and academic clinical trials testing promising and established drug and procedural interventions have failed to “beat” the placebo response. The collateral damage resulting from these failures is staggering; novel treatments, many with compelling mechanisms of action and promising Phase 2 trial results, never reach the patient, adversely affecting small and large pharma alike. Recent evidence suggests that variability in the placebo response may be attributed, in part, to genetic variation. Thus, having a better understanding of the genomic underpinnings of the placebo response, the determinants of the “placebome,” may pave the way to use placebos innovatively and more effectively in (1) drug development to reduce trial size and improve accuracy of drug efficacy determination, and (2) in the clinic to treat patients effectively. Harnessing the power of placebos challenges conventional wisdom. Hence, changing the clinical trial mindset requires a large volume of well-designed studies to test rigorously the effects of the placebome in past and future clinical trials. This unprecedented effort calls for broad collaborations among a diversity of experts from clinicians, biostatisticians, and neurobiologists, and computational biologists and bioethicists. This seminar brings together these experts to examine the evidence, discuss the potential, and weigh the pros and cons of developing the concept of genomically guided precision placebos.