In recent years, withdrawal of marketed drugs including sertindole, grepafloxacin, and terfenadine owing to prolongation of the length of time between the start of the Q wave and end of the T wave on an electrocardiogram (QT interval) has prompted considerable effort in trying to establish the molecular basis of this potentially lethal phenomenon. In the majority of cases, those chemical entities that prolong the QT interval and lead to torsades de pointes (TdPa) preferentially interact with a product of the human ether-a-go-go related gene (hERG), the R-subunit of IKr channels responsible for the rapid component of the delayed rectifier potassium current in the heart. 1-3 Consequently, throughout the pharmaceutical industry efforts to predict QT prolongation risk have been focused on assays testing in vitro hERG channel activity in mammalian cell lines expressing the hERG channel. Medicinal chemistry groups engaged in both hit-to-lead and lead optimization activities have encountered blockade of the hERG channel as a significant hurdle along the drug discovery trajectory. Despite this, an increasing body of information has been accumulated on the strategy and tactics for overcoming inhibition of hERG. A brief summary of the in silico, in vitro, and in vivo approaches employed to measure blockade of hERG and QT prolongation is detailed in this report. The purpose of the following discussion is to summarize the approaches engaged to circumvent activity at hERG, identified through an extensive literature survey. The optimizations are recorded as pairs of compounds, which have been categorized in terms of the tactics employed to diminish hERG activity. Examination of the properties of the compounds within each category has enabled formulation of some empirical guidelines. Conclusions and recommendations for future activities are also presented.