Here we provide the first genome-wide in vivo analysis of the Na + /Ca 2+ exchanger family in the model system Caenorhabditis elegans. We source all members of this family within the Caenorhabditis genus and reconstruct their phylogeny across humans and Drosophila melanogaster. Next, we provide a description of the expression pattern for each exchanger gene in C. elegans, revealing a wide expression in a number of tissues and cell types including sensory neurons, interneurons, motor neurons, muscle cells, and intestinal tissue. Finally, we conduct a series of behavioral and functional analyses through mutant characterization in C. elegans.From these data we demonstrate that, similar to mammalian systems, the expression of Na + /Ca 2+ exchangers in C. elegans is skewed toward excitable cells, and we propose that C. elegans may be an ideal model system for the study of Na + /Ca 2+ exchangers.C ALCIUM functions as a diverse signaling molecule in a variety of cell types through activation and conformational changes of proteins, as well as via modulation of cellular capacitance (Berridge et al. 2000(Berridge et al. , 2003Bootman et al. 2001). Neurotransmitter release, muscular contraction, apoptosis, and lymphocyte activation are some of the many cellular processes mediated by calcium signaling, and accordingly, strict balance of calcium levels must be maintained to prevent cellular dysfunction. Cells accomplish this primarily by extruding calcium through plasma membraneembedded plasma membrane Ca 2+ ATPase (PMCA) pumps and utilizing exchanger ion transporters. PMCA proteins are high-affinity/low-capacity pumps that maintain calcium homeostasis over sustained periods of time by removing one Ca 2+ ion for every ATP hydrolyzed (Tidow et al. 2012). Exchangers such as Na + /Ca 2+ exchangers (NCX), Na + /Ca 2+ /K + exchangers (NCKX), and calcium/cation exchangers (CCX) are low-affinity/high-capacity ion transporters that rapidly expel calcium ions (Philipson and Nicoll 2000;Philipson et al. 2002;Lytton 2007;Nicoll et al. 2013). The NCX, NCKX, and CCX families of exchangers comprise the three branches of the family of Na + /Ca 2+ exchangers in animals (Cai and Lytton 2004a,b;Lytton 2007). Under normal physiological conditions, NCX ion transporters utilize the energy stored in the transmembrane gradient to allow influx of three Na + ions and extrusion of one Ca 2+ ion (Hilge 2012;Ottolia and Philipson 2013). In the case of the NCKX transporter, there is one Ca 2+ and one K + ion exchanged in return for Na + ion influx, and in the case of the CCX exchangers, both Na + /Ca 2+ and Li + /Ca 2+ exchanges have been observed (Lytton. 2007;Visser and Lytton 2007). As of yet, the nematode Caenorhabditis elegans has not been used as an in vivo model organism to study the NCX, NCKX, CCX exchanger family. Here we provide a detailed description of the phylogeny of this family of transporters in C. elegans, examine the expression patterns of each member, and uncover roles for one NCX member and one CCX member in muscle contracti...