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A resolution enhanced NaI(Tl)-scintillator micro-SPECT device using a pin hole collimator geometry has been built and tested with small animals. This device was constructed based on a depth-of-interaction (DOI) measurement using a thick scintillator crystal and a position sensitive PMT to measure depth dependent scintillator light profiles. DOI measurement eliminates the parallax error that degrades the high spatial resolution required for small animal imaging. This novel technique for 3D gamma-ray detection was incorporated into a micro-SPECT device and tested with a 57Co source and 98mTc-MDP in mice. We are now investigating the combination of micro-SPECT with 3D optical imaging, so that the interaction of different biological aspects can be studied by each technique. A simple application permits a 3D reconstruction of the animal's skin surface thus enhancing visualization and making possible depth-dependent corrections and a quantitative description of biological processes can be achieved. The combination of micro-SPECT and 3D optical imaging, including bioluminescence 3D reconstruction, opens new avenues in multi-modality imaging for biology and medicine.