The short QT syndrome (SQTS) is a rare but dangerous condition that is associated with accelerated ventricular repolarisation and that carries a risk of potentially fatal ventricular arrhythmias (Patel et al., 2010). The SQT1-SQT3 variants of the syndrome are associated with mutations to KCNH2 (hERG), KCNQ1 (KvLQT1) and KCNJ2 that lead to increased repolarising ionic currents through channels responsible, respectively, for IKr, IKs and IK1 (Patel et al, 2010). At present there are no animal models of SQT1-SQT3 that incorporate the precise ion channel current alterations that have been identified through the in vitro study of recombinant SQTS mutant K+ channels. Consequently, we have adopted a computer simulation approach in order to investigate electrophysiological changes that may increase arrhythmia susceptibility in the SQTS (Zhang et al., 2008; Adeniran et al., 2011; Adeniran et al., 2012). The properties of each of IKr, IKs and IK1 in human ventricular cell models were in turn altered, to recapitulate changes observed in in vitro studies of SQT1-3 mutant channels (respectively N588K-hERG, V307L-KCNQ1, D172N-Kir2.1). The resulting cell models were then incorporated into one-, two- and three-dimensional ventricular tissue models that considered ventricular transmural electrical heterogeneity of endocardial, midmyocardial and epicardial cell regions. The intact tissue model recapitulated QT interval shortening with each SQT mutant, confirming that the current alterations arising from these gain-of-function mutations are causally linked to QT interval shortening (Zhang et al., 2008; Adeniran et al., 2011; Adeniran et al., 2012). Effective refractory period (ERP) shortening was observed for each SQTS variant and in tissue simulations alterations to transmural dispersion of repolarization were also observed (Zhang et al., 2008; Adeniran et al., 2011; Adeniran et al., 2012). Tissue vulnerability to genesis of re-entry was increased and the lifespan of re-entrant spiral waves was also increased in the SQT variant simulation conditions (Zhang et al., 2008; Adeniran et al., 2011; Adeniran et al., 2012). Thus, the changes to repolarising K+ currents resulting from SQT1-3 linked channel defects increase susceptibility to the genesis and maintenance of re-entrant arrhythmia.