There has been considerable recent disappointment with the failure of a number of major new pharmacological strategies for the treatment of chronic heart failure. In turn, there has been much speculation as to why trials of these therapies have not shown benefit. Among a number of plausible and scientifically valid reasons, consideration should be afforded to the potential contribution of "regression to the truth." Regression to the truth derives from the biological concept of regression to the mean, whereby random fluctuations in a biological variable occur over time, such that the true value of the variable is approached with repeated measurements. This same concept can be applied to clinical trial programs for new drugs for heart failure. Because only strongly positive trials generally go on to phase III testing, and some of these early phase studies are positive by chance alone, on retesting in phase III the results are very likely not be as strongly positive. Numerous examples of regression to the truth apply for trials of heart failure therapies, as well as in other areas. A major concern is how to minimize negative outcomes in phase III trials. One approach is to perform major rigorous phase II testing. Alternatively, avoidance of phase II testing will minimize "regression to the truth" because there are no data in phase II from which regression might occur. However, this approach does not obviate the need for an evaluation process in the selection of candidate agents (and their appropriate dose) in order to proceed to definitive testing.