Abnormalities in G-protein-gated inwardly rectifying potassium (GIRK) channels have been implicated in diseased states of the cardiovascular system; however, the role of GIRK4 (Kir3.4) in cardiac physiology and pathophysiology has yet to be completely understood. Within the heart, the KAChchannel, consisting of two GIRK1 and two GIRK4 subunits, plays a major role in modulating the parasympathetic nervous system’s influence on cardiac physiology. Being that GIRK4 is necessary for the functional KAChchannel,KCNJ5, which encodes GIRK4, it presents as a therapeutic target for cardiovascular pathology. Human variants inKCNJ5have been identified in familial hyperaldosteronism type III, long QT syndrome, atrial fibrillation, and sinus node dysfunction. Here, we explore the relevance ofKCNJ5in each of these diseases. Further, we address the limitations and complexities of discerning the role ofKCNJ5in cardiovascular pathophysiology, as identical human variants ofKCNJ5have been identified in several diseases with overlapping pathophysiology.