The N-methyl-D-aspartate receptor (NMDAR) plays a crucial role in shaping the strength of synaptic connections. Over the last decades, extensive studies have defined the cellular and molecular mechanisms by which synaptic NMDARs control the maturation and plasticity of synaptic transmission, and how altered synaptic NMDAR signaling is implicated in neurodegenerative and psychiatric disorders. It is now clear that activation of synaptic or extrasynaptic NMDARs produces different signaling cascades and thus neuronal functions. Our current understanding of NMDAR surface distribution and trafficking is only emerging. Exchange of NMDARs between synaptic and extrasynaptic areas through surface diffusion is a highly dynamic and regulated process. The aim of this review is to describe the identified mechanisms that regulate surface NMDAR behaviors and discuss the impact of this new trafficking pathway on the well-established NMDAR-dependent physiological and pathophysiological processes.