Na(+)/Ca(2+)-K(+) exchangers (NCKX), alongside the more widely known Na(+)/Ca(2+) exchangers (NCX), are important players in the cellular Ca(2+) toolkit. But, unlike NCX, much less is known about the physiological roles of NCKX, while emergent evidence indicates that NCKX has highly specialized functions in cells and tissues where it is expressed. As their name implies, there are functional similarities in the properties of the two Ca(2+) exchanger families, but there are specific differences as well. Here, we compare and contrast their key functional properties of ionic dependence and affinities, as well as report on the effects of KB-R7943 - a compound that is widely used to differentiate the two exchangers. We also review structural similarities and differences between the two exchangers. The aim is to draw attention to key differences that will aid in differentiating the two exchangers in physiological contexts where both exist but perhaps play distinct roles.