Two discoveries have put D-serine in the spotlight of neuroscience. First, D-serine was detected in brain tissue at high levels. Second, it was found to act on the N-methyl-D-aspartate receptor (NMDAR). This receptor is central to use-dependent synaptic plasticity, the cellular process which is widely believed to underlie learning. The ensuing quest for the mechanisms of D-serine synthesis, release and clearance, as well as for its physiological significance has provided a wealth of experimental evidence implicating D-serine in synaptic plasticity. However some key questions remain unanswered. Which cells release D-serine and upon what stimuli? Is D-serine supply dynamically regulated? What is the fate of released D-serine? Answering these questions appears to be an essential step in our understanding of how NMDARs trigger synaptic plasticity and learning. This review will highlight some recent advances and avenues of enquiry in dynamic D-serine signaling in the mammalian brain with emphasis on neurophysiology.