Immune synapses (IS) are supramolecular clusters providing intercellular communication among cells of the immune system. While the physiological role and consequences of IS formation are beginning to be understood, these studies have given rise to a new research topic in the biology of lymphocyte interactions: synaptic transfer of proteins between lymphocytes. During natural killer (NK) cell immunosurveillance, clustering and transfer of receptor and ligand molecules have been observed at both the inhibitory and cytotoxic NK cell immune synapse (NK-IS). The transfer of activating receptors seems to be associated with receptor distribution to thin membrane connective structures (MCS)/nanotubes that communicate effector and susceptible target cells. Strikingly, bidirectional transfer of the activating receptor NKG2D and its cellular ligand MICB correlates with a reduction in NK cell cytotoxic function. In this regard, synaptic uptake of MICB may represent a novel strategy of tumor immune evasion. Finally, synaptic acquisition of receptors by NK cells may also favor the spread of pathogens. In this review we discuss possible mechanisms of synaptic protein transfer and propose different testable hypotheses about the physiological and pathological significance of this process for NK cell function.--Roda-Navarro, P., Reyburn, H. T. Intercellular protein transfer at the NK cell immune synapse: mechanisms and physiological significance.