Although the ICH E14 Guidance [1] was adopted in 2005 there is still much debate on the appropriate baseline needed to adjust for the variable nature of the QT interval and its heart rate corrected value (QTc) in the parallel Thorough QT (TQT) study. Numerous reports have documented the influence of circadian rhythm [2], food ingestion [3], sleep [4], and autonomic tone [5] on the QT/QTc interval. In the absence of baseline measurements, these factors can make it difficult to interpret QT effects of the study drug. In this issue of Drug Safety Dr. Zhang and colleagues [6] advocate the use of a time-matched baseline in parallel TQT studies to maximize the precision and accuracy of point estimates for QTc effects. Their recommendation is based on analyses of commonly used baseline correction methods using a large data set of parallel TQT studies submitted to the FDA for statistical review by sponsors. One assumption in the choice of baseline is that it should have no influence on the magnitude of QT effects (high accuracy) and it should minimize the uncertainty of the effects (high precision). Both accuracy and precision are important for the interpretation of a TQT trial. As a result, there is much focus on the implications of using different baseline adjustments in the parallel TQT study and understanding the role each baseline definition can have in determining the outcome of the trial as either positive or negative. The distinction between a positive or negative TQT study is based on the upper bound of the 95 % one-sided confidence interval (CI) for the largest time-matched mean difference in QTc between drug and placebo (baseline adjusted). If these (double-delta) DDQTc values exclude 10 ms at all study times the result is a negative TQT study [1]. Intensive ECG monitoring is then hardly ever required in subsequent trials (phase II/III). Conversely, drugs for which an effect exceeding 10 ms cannot be excluded almost always require additional QT interval monitoring in target patients including dose-concentration effects, outlier analysis, changes in mean QTc values, analysis of QTc in subgroups of interest, and identification of individuals who develop a markedly prolonged QTc. The need for additional ECG monitoring in late phase trials can add millions to drug development and may ultimately pose financial limitations on the number of medications which can be developed [7]. The importance of correctly adjusting for baseline in the TQT study is therefore evident.