The Nm23/NME gene family has been under intensive study since Nm23H1/NME1 was identified as the first metastasis suppressor. Inverse correlation between the expression levels of NME1/2 and prognosis has indeed been demonstrated in different tumor cohorts. Interestingly, the presence of NME proteins in the extracellular environment in normal and tumoral conditions has also been noted. In many reported cases, however, these extracellular NME proteins exhibit anti-differentiation or oncogenic functions, contradicting their canonical anti-metastatic action. This emerging field thus warrants further investigation. In this review, we summarize the current understanding of extracellular NME proteins. A role in promoting stem cell pluripotency and inducing development of central nervous system as well as a neuroprotective function of extracellular NME have been suggested. Moreover, a tumor-promoting function of extracellular NME also emerged at least in some tumor cohorts. In this complex scenario, the secretory mechanism through which NME proteins exit cells is far from being understood. Recently, some evidence obtained in the Drosophila and cancer cell line models points to the involvement of Dynamin in controlling the balance between intra- and extracellular levels of NME. Further analyses on extracellular NME will lead to a better understanding of its physiological function and in turn will allow understanding of how its deregulation contributes to carcinogenesis.