Calcium homeostasis modulator 1 (CALHM1) has been recently identified as a pore-forming subunit of a novel plasma membrane ion channel with unusual properties and important physiological roles. Previously known as FAM26C, it belongs to a family of six genes expressed throughout vertebrates. C. elegans expresses the only CALHM1 homolog, clhm-1. Both CALHM1 and CLHM-1 ion channels are regulated by membrane potential and extracellular Ca²⁺. Analysis of the permeability properties of CALHM1 revealed that its pore acts as a molecular sieve, with permeation determined by ion size. Similar to gap-junction forming connexins, CALHM1 channels are permeable to cations and monovalent anions, have a functional ion-conducting pore diameter of ~14 Å, and are composed of a hexamer of CALHM1 monomers. Through convergent evolution, CALHM1 has additional structural features that are reminiscent of the connexin and pannexin/innexins gene families, including four transmembrane helices, an amino-terminal helix and extracellular cysteine residues. Mouse CALHM1 plays an important role in mediating low-[Ca²⁺]_o-induced cortical neuron excitability. In C. elegans, genetic deletion of clhm-1, which is expressed in sensory neurons and body wall muscle cells, causes locomotion defects. In mammals, CALHM1 is expressed in sweet/bitter/umami-sensing taste bud cells in the tongue, where it mediates tastant-evoked release of neurotransmitter, ATP, onto the afferent gustatory nerve fibers, by a non-exocytotic, voltage-gated ion channel mechanism. Genetic elimination of Calhm1 in mice abolishes tastant-evoked ATP release and the ability of the animals to perceive sweet, bitter and umami tastes, establishing an essential role for CALHM1 in taste perception. We discuss structure, function and physiological roles of CALHM1 channel, as well as recent findings on other CALHM isoforms that we believe are key players in physiological ATP releases with unknown molecular mechanisms.