The neuroplastins np65 and np55 are neuronal and synapse-enriched immunoglobulin (Ig) superfamily cell adhesion molecules that contain 3 and 2 Ig domains, respectively. Np65 is neuron specific whereas np55 is expressed in many tissues. They are multifunctional proteins whose physiological roles are defined by the partner proteins they bind to and the signalling pathways they activate. The neuroplastins are implicated in activity-dependent long-term synaptic plasticity. Thus neuroplastin-specific antibodies and a recombinant peptide inhibit long-term potentiation in hippocampal neurones. This is mediated by activation of the p38MAP kinase signalling pathway, resulting in the downregulation of the surface expression of GluR1 receptors. Np65, but not np55, exhibits trans-homophilic binding. Both np65 and np55 induce neurite outgrowth and both activate the FGF receptor and associated downstream signalling pathways. Np65 binds to and colocalises with GABA(A) receptor subtypes and may play a role in anchoring them to specific synaptic and extrasynaptic sites. Most recently the neuroplastins have been shown to chaperone and support the monocarboxylate transporter MCT2 in transporting lactate across the neuronal plasma membrane. Thus the neuroplastins are multifunctional adhesion molecules which support neurite outgrowth, modulate long-term activity-dependent synaptic plasticity, regulate surface expression of GluR1 receptors, modulate GABA(A) receptor localisation, and play a key role in delivery of monocarboxylate energy substrates both to the synapse and to extrasynaptic sites. The diverse functions and range of signalling pathways activated by the neuroplastins suggest that they are important in modulating behaviour and in relation to human disease.