Nm23-H1 originally was discovered on the basis of its reduced RNA expression in very highly metastatic murine melanoma cell lines. Since that time, it has been shown to reduce the metastatic potential of highly aggressive tumors and to be an indicator of poor patient prognosis in many cancer types. Although LOH of NME1 is prevalent in many tumors, this event does not predict reliably the overall levels of Nm23-H1 expression and therefore cannot be used as a genetic screen for the aggressive potential of a cancer. In addition, mutant forms of the gene exist; however, expression patterns seem to be the key to the differences observed between tumor cells of high and low metastatic potential. Differential Nm23-H1 expression may reflect transcriptional regulation and/or the stability of the Nm23-H1 transcript. The mechanism of action of the protein is still unknown; however, the protein does possess a unique kinase activity that is essential in other organisms. The histidine protein-kinase activity is the sole known activity that correlates tightly with the ability of Nm23-H1 to suppress cell motility. The identification of other components comprising this signaling pathway will be the next step toward unraveling the mysteries of this metastasis suppressor.