The cardiac I(Ks) current is involved in action potential repolarization, where its primary function is to limit action potential prolongation during sympathetic stimulation. The I(Ks) channel is mainly composed of K(V)7.1 ion channels associated with KCNE1 auxiliary subunits. The availability of KCNE1 solution structure by nuclear magnetic resonance spectroscopy in conjunction with biochemical assays addressing K(V)7.1-KCNE1 residue interactions has provided new insights into the structural basis for K(V)7.1 modulation by KCNE1. Recent evidence further suggests that KCNE2 may associate with the K(V)7.1-KCNE1 channel complex and modulate its current amplitude. Here we review recent studies in this area and discuss potential roles for multiple KCNE(x) subunits in I(Ks) generation and modulation as well as the clinical relevance of the new information.