Conventional single photon emission computed tomography (SPECT) relies on mechanical collimation whose resolution and sensitivity are interdependent, the best performance a SPECT system can attain is only a compromise of these two equally desired properties. To simultaneously achieve high resolution and sensitivity, we propose to use sensitive detectors constructed in a multi-layer in ter spaced mosaicdetectors (MATRICES) architecture to accomplish part of the collimation needed. We name this new approach self-collimation. We evaluate three self-collimating SPECT systems and report their imaging performance: 1) A simulated human brain SPECT achieves 3.88% sensitivity, it clearly resolves 0.5-mm and 1.0-mm hot-rod patterns at noise-free and realistic count-levels, respectively; 2) a simulated mouse SPECT achieves 1.25% sensitivity, it clearly resolves 50- [Formula: see text] and 100- [Formula: see text] hot-rod patterns at noise-free and realistic count-levels, respectively; 3) a SPECT prototype achieves 0.14% sensitivity and clearly separates 0.3-mm-diameter point sources of which the center-to-center neighbor distance is also 0.3 mm. Simulated contrast phantom studies show excellent resolution and signal-to-noise performance. The unprecedented system performance demonstrated by these 3 SPECT scanners is a clear manifestation of the superiority of the self-collimating approach over conventional mechanical collimation. It represents a potential paradigm shift in SPECT technology development.