Cancer is a group of neoplastic diseases that shares as common feature uncontrolled cellular proliferation. Tumorigenesis and cancer progression are mediated by genetic mutations and epigenetic regulation, which provides proliferative advantages to the tumor cells, including unlimited proliferation, genetic instability, independence of growth signals, escape from immune system, evasion of apoptosis, invasiveness, and metastatic capacity. Among the alterations enabling these hallmarks of cancer, metabolic reprogramming and disrupted ionic homeostasis are highlighted. Calcium (Ca2+) participates as a cofactor in several reactions of metabolism and in signaling pathways, playing crucial roles in cell physiology. However, tumor cells exhibit alterations in regulatory mechanisms of Ca2+ homeostasis. Although alterations in the expression and activity of different Ca2+ transporters, pumps, and channels have been studied in cancer, the involvement of Na+/Ca2+ exchanger (NCX) is still poorly investigated. NCX is an antiporter in plasma membrane that promotes Ca2+ efflux and Na+ influx, referred as forward mode. Conversely, Ca2+ influx/Na+ efflux (reverse mode) can occur in some situations. Recent studies have provided evidence about changes in the expression and activity of NCX in several types of cancer. The expression of NCX has been reported to be higher in tumor cells compared to normal counterpart, and its expression level seems to correlate with the malignancy degree. Functionally, predominance of the reverse mode of NCX in tumor cells has been proposed, but further studies are required to elucidate the underlying mechanisms. In this chapter, expression and functional aspects of NCX in cancer will be presented.