In this critical review we discuss recent advances in understanding the modes of interaction of metal ions with membrane proteins, including channels, pumps, transporters, ATP-binding cassette proteins, G-protein coupled receptors, kinases and respiratory enzymes. Such knowledge provides a basis for elucidating the mechanism of action of some classes of metallodrugs, and a stimulus for the further exploration of the coordination chemistry of metal ions in membranes. Such research offers promise for the discovery of new drugs with unusual modes of action. The article will be of interest to bioinorganic chemists, chemical biologists, biochemists, pharmacologists and medicinal chemists. (247 references)