Technetium-99m sestamibi is a new agent that offers several theoretical advantages over Tl-201 for myocardial perfusion imaging. The results of current clinical trials utilizing acquisition and processing parameters similar to those of Tl-201 and a separate 2-day injection protocol suggest that Tc-99m sestamibi and T1-201 SPECT provide similar information with respect to the detection of myocardial perfusion defects, the assessment of the pattern of defect reversibility, the overall detection of CAD, and the detection of disease in individual coronary arteries. Tc-99m sestamibi SPECT appears to be superior to Tc-99m planar imaging because it provides a higher defect contrast and is more accurate for the detection of disease in individual coronary arteries. Significant research is underway to address optimization of acquisition and processing of Tc-99m sestamibi studies and the development of quantitative algorithms for detection and localization of CAD and sizing of transmural and nontransmural myocardial perfusion defects. It is expected that with the implementation of the final results of these new developments, further significant improvement in image quality will be attained, which, in turn, will increase the confidence of image interpretation. The development of algorithms for analysis of diastolic myocardial images may allow better evaluation of small and nontransmural myocardial defects. Furthermore, gated studies may provide valuable information with respect to regional myocardial wall motion, wall thickening, and artifact identification. Simultaneous assessment of ventricular function by performing first-pass studies may provide important information additional to that obtained from analysis of myocardial perfusion, especially in relation to the prognostic significance of different myocardial perfusion patterns. With the implementation of algorithms for attenuation and scatter correction, the overall specificity of Tc-99m sestamibi SPECT should improve significantly because of a substantial decrease in the instances of attenuation-related image artifacts.