The plasma membrane phosphoinositide phosphatidylinositol 4,5-bisphosphate (PIP₂) controls the activity of most ion channels tested thus far through direct electrostatic interactions. Mutations in channel proteins that change their apparent affinity to PIP₂ can lead to channelopathies. Given the fundamental role that membrane phosphoinositides play in regulating channel activity, it is surprising that only a small number of channelopathies have been linked to phosphoinositides. This review proposes that for channels whose activity is PIP₂-dependent and for which mutations can lead to channelopathies, the possibility that the mutations alter channel-PIP₂ interactions ought to be tested. Similarly, diseases that are linked to disorders of the phosphoinositide pathway result in altered PIP₂ levels. In such cases, it is proposed that the possibility for a concomitant dysregulation of channel activity also ought to be tested. The ever-growing list of ion channels whose activity depends on interactions with PIP₂ promises to provide a mechanism by which defects on either the channel protein or the phosphoinositide levels can lead to disease.