Physical and emotional stress is accompanied by release of stress hormones such as the glucocorticoid cortisol. This hormone upregulates the serum- and glucocorticoid-inducible kinase 1 (SGK1) which in turn stimulates IKs, a slow delayed rectifier potassium current that mediates cardiac action potential repolarization. Mutations in I_Ks channel alpha (KCNQ1, KvLQT1, Kv7.1) or beta (KCNE1, IsK, MinK) subunits cause long QT syndrome (LQTS), an inherited cardiac arrhythmia associated with increased risk of sudden death. Together with the GTPases RAB5 and RAB11, SGK1 facilitates membrane recycling of KCNQ1 channels. Here, we show altered SGK1-dependent regulation of LQTS-associated mutant IKs channels. While some mutant KCNQ1 channels had reduced basal activity but were still activated by SGK1, currents mediated by KCNQ1(Y111C), KCNQ1(L114P) or KCNE1(D76N) were paradoxically reduced by SGK1. Mutagenesis experiments indicate that stimulation of I_Ks channels by SGK1 depends on a HxNDP motif in KCNE1. Identification of the I_Ks recycling pathway and its modulation by stress-stimulated SGK1 provides novel mechanistic insight into potentially fatal cardiac arrhythmias triggered by physical or psychological stress.