Ion channels and G protein-coupled receptors (GPCRs) are integral transmembrane proteins vital to a multitude of cell signaling and physiological functions. Members of these large protein families are known to interact directly with various intracellular protein partners in a dynamic and isoform-dependent manner, ultimately shaping their life cycle and signal output. The family of G protein-gated inwardly rectifying potassium channels (Kir3 or GIRK) expressed in brain, heart, and endocrine tissues were recently shown to stably associate with several different GPCRs, forming the basis of a macromolecular ion channel-GPCR signaling complex. The molecular determinants that mediate and maintain GPCR-Kir3 channel complexes are currently not well understood. Recent findings and emerging hypotheses on the assembly and stability of multiprotein GPCR-Kir channel signaling complexes are discussed, highlighting distinct mechanisms used by different Kir channel families. These protein-protein interaction processes are crucial in determining both the synaptic response times and the extent of GPCR "cross-talk" in Kir3-mediated inhibitory synaptic transmission.