G protein-modulated inwardly rectifying potassium channels (Kir3, GIRK) are crucial integrators of G protein-coupled receptor (GPCR) signalling and play key roles in the stabilization of resting membrane potential in excitable and non-excitable cells. Here we discuss their roles in the heart, with a specific focus on how they might be involved in two types of cardiac arrhythmia, atrial fibrillation and long QT syndrome. Further, they may be important in the off-target effects of several different drugs. Finally, we argue that although GPCRs and effectors like Kir3 channels might be interesting individual drug targets, we should start thinking about targetting them as complexes, with a view towards developing more selective drugs for specific clinical indications.