Six-transmembrane (6-TM) cation channels are plasma membrane-integral components of cellular signaling pathways conserved in almost all species, including animals, plants and some kinds of prokaryotes. These channels selectively permeate cations in response to various signals. In excitable and non-excitable mammalian cells, 6-TM cation channels play fundamental roles, including the generation of action potential and its transmission, the regulation of intracellular ion concentrations, and the activation of signaling cascades by humoral or mechanical pathways. Recently, the structures of three different 6-TM-type cation channels have been determined using single-particle analysis from cryo-electron microscopy images: the voltage-sensitive sodium channel, the IP(3) receptor and the TRPC3 channel. The basic structure of the molecules is similar: a bell-like shape comprising a relatively small extracellular (or luminal) domain, a protein-dense transmembrane domain and an expanded cytoplasmic domain. However, in detail, the cytoplasmic architectures are different from one another and are diversely evolved to their specific physiological functions.