<p>In recent years, cryo-electron microscopy structures of ion channels in complex with G proteins have been resolved, providing insights into the molecular mechanisms underlying the crosstalk between G protein-coupled receptors (GPCRs) and ion channels. Downstream signaling initiated by GPCR activation can indirectly modulate ion channel activity. Alternatively, the direct binding of Gα or Gβγ subunits to ion channels can directly regulate their ion conduction activity. Recent cryo-electron microscopy structures, such as TRPC5–Gα_i3, GIRK–Gβγ and TRPM3–Gβγ, have elucidated these direct interactions and advanced our understanding of how Gα or Gβγ subunits activated by GPCRs modulate ion channel activity. In addition, the structure of the TRPV4–RhoA complex has revealed that small G proteins can also directly modulate ion channels. Understanding the physiological roles of these complexes will be critical for their potential use as pharmacological targets. Here we summarize the current knowledge of the interactions between ion channels and G proteins.</p>