Nucleoside diphosphate kinases (NDPKs/NDK/NME) are a multifunctional class of proteins conserved throughout evolution. Whilst many of the functions of NDPKs have been identified as intracellular, extracellular eukaryotic and prokaryotic NDPK proteins are also detected in multiple systems and have been implicated in both normal physiology and disease. This review provides an overview of where the field stands on our developing understanding of how NDPK proteins get out of cells, the physiological role of extracellular NDPKs, and how extracellular NDPKs may signal to cells. We will also discuss some of the unanswered questions, the 'known-unknowns' that particularly warrant further investigation.