Chronic kidney disease is assuming epidemic proportions, and an increasing number of clinical trials are testing treatments developed to improve morbidity and mortality. Surprisingly, however, a large proportion of these trials have had negative or neutral results. When trials unexpectedly demonstrate either no benefit or a detrimental impact of a treatment, especially when that treatment is already used in practice, critics commonly argue that the results were dictated by flawed trial design rather than the intrinsic properties of the treatment. In kidney disease therapeutics, trials commonly rely on observational data and test the hypothesis that these associations may be extrapolated to cause-and-effect. Other key issues in trial design that may affect outcomes include the impact of enrolling relatively healthier subjects, the complexity of recruiting participants with specific characteristics while maintaining generalizability, and the subtleties of event adjudication and quality of life assessments. In this article, general principles of trial design will be discussed and the potential lessons learned from recent trials in nephrology will be critically reviewed.