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Introduction Ischemic heart disease is the leading cause of mortality globally, with multivessel disease (MVD) identified in 40-50% of patients presenting with Acute Coronary Syndrome (ACS). Current European and American guidelines recommend complete revascularisation (CR) for ST-elevation myocardial infarction (STEMI), replacing historical ‘culprit-only’ conservatism rooted in safety concerns. Restraint stemmed from risks of prolonged procedures, nephropathy, and the acute pro-thrombotic setting. However, recent randomised controlled trials (RCTs) suggest that leaving residual atherosclerotic lesions untreated drives recurrent ischemic events. This review evaluates CR versus culprit-only PCI to define the optimal strategy across the ACS spectrum.Methods Medline, Embase, and Cochrane databases were searched for landmark RCTs and large-scale registries (2013-2026). Two independent reviewers included primary studies evaluating CR versus culprit-only PCI strategies in patients with STEMI, non-ST-elevation ACS (NSTE-ACS), and cardiogenic shock. Primary outcomes included cardiovascular mortality (CV), myocardial infarction (MI), and revascularisation strategies. Key studies included PRAMI, DANAMI-CPRIMULTI, COMPARE-ACUTE, COMPLETE, FLOWER-MI, MULTISTARS AMI, FIRE, and PREVENT, alongside observational data from the Netherlands Heart Registry.Results In STEMI, the COMPLETE trial (n=4,041) demonstrated CR superiority, reducing CV death or new MI by 26% (HR 0.74, P=0.004). Regarding timing, MULTISTARS AMI (n=840) indicated that immediate CR is non-inferior to staged intervention (RR 0.52, P<0.001), reducing the risk of inter-stage ischemic events. In adults >75 years, the FIRE trial (n=1,445) confirmed physiology-guided CR significantly reduced death/ischemic events (HR 0.73, P=0.01) without safety penalties. Conversely, in NSTE-ACS, registry data (n=10,507) indicate CR reduces repeat revascularisation (HR 0.57) but lacks a mortality benefit. FLOWER-MI showed no benefit of FFR over angiography (HR 1.32, P=0.31), indicating anatomical plaque burden may be as prognostically relevant as flow. The PREVENT trial (n=1,606) challenged the requirement for ischemia entirely, demonstrating that preventive PCI of non-flow-limiting (FFR >0.80) but biologically vulnerable plaques reduced major adverse cardiac events compared to optimal medical therapy (0.4% vs 3.4%, P=0.0003).Conclusion While CR is the current standard of care in stable and elderly STEMI patients, significant heterogeneity remains regarding lesion assessment. The divergence between FFR and angiographic outcomes in FLOWER-MI, combined with the success of preventive stenting in PREVENT, implies that flow limitation is an imperfect indicator for risk in inflamed coronaries. Future revascularisation strategies must therefore pivot from ‘lumenology’ to the identification of biological vulnerability, ensuring that intervention targets lesions prone to rupture rather than merely restricting flow.