One of the major strengths of nuclear myocardial perfusion imaging (MPI) is the robust prognostic databases from observational studies demonstrating significantly different outcomes in patients with low-risk vs high-risk scans. The severity of the MPI defect can be semi-quantitated using the summed stress score (SSS) and summed difference score (SDS). SSS is more strongly associated with mortality, whereas SDS is the better predictor of subsequent coronary angiography and revascularization. The strength of MPI variables as prognostic indicators decreases when adjusted for prognostically important clinical and stress test variables. Nonetheless, most studies of general patient populations have demonstrated that MPI adds incremental prognostic value to clinical and stress test information. In contrast to these positive results from observational studies, the application of MPI ischemia as a treatment guide in several recent trials (DIAD, WOMEN, COURAGE, BARI 2D, STICH) has largely failed to identify patient subsets with improved outcome. This issue will continue to be investigated in the ongoing PROMISE and ISCHEMIA trials.