Clinical trials, especially the randomized clinical trial, have been and will remain the gold standard for the evaluation of new interventions, including pharmaceuticals, biologics, medical devices, procedures, or behavioral modifications. Despite more than five decades of experience, there are still challenges in their design, conduct, monitoring, and analyses. Some of these challenges remain and some are emerging, in part due to the progress in genomics and proteomics. These issues may be statistical, logistical, or a combination. Included are follow-up of subjects who withdraw from intervention, the proposed use of recent adaptive designs, implementing noninferiority designs, reliance on surrogate markers, and gene transfer studies. Comparative effectiveness studies are of increasing interest but present major design and analysis issues. Forces external to the trial are also becoming more common. Copyright © 2012 John Wiley & Sons, Ltd.