Ion channels are integral membrane proteins that enable the passive flow of inorganic ions by forming hydrated pores across biological membranes. Their pore-forming alpha subunits determine ion permeation and provide the machinery for gating. In addition, channel class specific accessory proteins termed beta, gamma and delta subunits have been found that modulate or even determine key properties like channel gating (e.g. activation, inactivation properties), surface expression, targeting and stability. Moreover, some of these subunits constitute binding sites for toxins as well as for therapeutic drugs. With the development of more powerful proteomic and molecular biology-based methods, a vastly increasing number of proteins interacting with ion channels has recently been described. These results are providing novel insight into ion channel function and at the same time challenging classical concepts of beta subunits and ion channel drug targets. They are also raising questions about functional validation and reliability of these methods. This review focuses on the potentials and limitations of modern “-omic” protein-protein interaction analyses and their application to ion channels. After recapitulating fundamental thermodynamic and biochemical principles underlying protein-protein interactions, current methods for their systematic identification are critically reviewed. Selected examples of newly characterized ion channel complexes will then be discussed to illustrate the implications for molecular understanding as well as for the effective selection and screening of ion channel drug targets.