N-methyl-D-aspartate receptors (NMDARs) are involved in higher cognitive function of the brain, but also in the disease mechanisms of several neurological disorders. Over the past three decades, several groups have worked on the development of tracers for imaging NMDARs with single photon emission computed tomography (SPECT) or positron emission tomography (PET). These tracers only bind to open receptors, and thereby reflect both receptor density and activation status. It is not always straightforward to determine the level of specificity in the binding of an NMDAR tracer, and controversial findings have been reported. Quantification of tracer binding requires dynamic imaging and kinetic analysis. As NMDARs are ubiquitous in the brain, there is no reference region, and absolute quantification, based on a metabolite-corrected arterial input function, is needed. Despite a series of difficulties, multiple clinical conditions have been investigated using both SPECT and PET NMDAR tracers.