For patients presenting with an acute ST-segment–elevation myocardial infarction, the most effective therapy for reducing myocardial infarct size and preserving left ventricular systolic function is primary percutaneous coronary intervention (PPCI). However, mortality and morbidity remain significant. This is partly attributed to the development of microvascular obstruction, which occurs in around 50% of ST-segment–elevation myocardial infarction patients post-PPCI, and it is associated with adverse left ventricular remodeling and worse clinical outcomes. Although microvascular obstruction can be detected by cardiac imaging techniques several hours post-PPCI, it may be too late to intervene at that time. Therefore, being able to predict the development of microvascular obstruction at the time of PPCI may identify high-risk patients who might benefit from further adjuvant intracoronary therapies, such as thrombolysis, vasodilators, glycoprotein IIb/IIIa inhibitors, and anti-inflammatory agents that may reduce microvascular obstruction. Recent studies have shown that invasive coronary physiology measurements performed during PPCI can be used to assess the coronary microcirculation. In this article, we provide an overview of the various invasive methods currently available to assess the coronary microcirculation in the setting of ST-segment–elevation myocardial infarction, and how they could potentially be used in the future for tailoring therapies to those most at risk.