Marked QT prolongation and torsades de pointes can occur not only in the congenital long QT syndromes (LQTSs) but also as a consequence of environmental stimuli, notably administration of certain drugs. A key feature of this ‘acquired’ form of the LQTS has been its unpredictable nature. That is, although risk factors have been identified in series of patients, they have not been terribly useful in addressing risk in an individual patient. Normal cardiac repolarization depends critically on the interplay of multiple ion currents, and these provide some redundancy, or ‘reserve’, to protect against excessive QT prolongation by drugs. We have proposed that lesions in these repolarizing mechanisms can remain subclinical but nevertheless increase risk on drug exposure, and have termed this situation ‘reduced repolarization reserve’. The evidence in support of this concept is presented, and the known and potential contributions by genetic variants to risk is examined. Assessing variability in susceptibility to acquired LQTS provides a framework for analysis of other complex gene–environment interactions.