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Background: The integration of global longitudinal strain (GLS) with stress echocardiography (SE) represents a significant advancement in non-invasive cardiac diagnostics, particularly in the evaluation of coronary artery disease (CAD). GLS, derived from speckle-tracking echocardiography, quantifies myocardial deformation and offers superior sensitivity for detecting subclinical myocardial dysfunction compared to conventional metrics like wall motion and ejection fraction. Recent studies have validated the prognostic and diagnostic efficacy of GLS both at rest and during stress, notably enhancing the detection of obstructive and non-obstructive CAD, microvascular dysfunction, and other cardiac pathologies. Methods: This manuscript synthesizes extensive clinical data demonstrating the added value of GLS during stress echocardiography across diverse cardiac conditions—including valvular heart disease, heart failure, cardio-oncology, and pediatric cardiology. Novel metrics like longitudinal strain reserve (LSR), myocardial work indices, and post-systolic strain have further enriched risk stratification strategies. Results: The combination of GLS with SE has been shown to approximate the accuracy of invasive coronary angiography in intermediate-risk patients and in cases with equivocal traditional SE findings. Despite its clinical promise, the utility of GLS is challenged by technical limitations, including image quality dependency, inter-vendor variability, and limited applicability during high heart rate states. Conclusions: As technological refinement and standardization progress, GLS integrated with SE is poised to become a mainstay in precision cardiology, improving diagnostic yield, guiding therapeutic decisions, and enhancing patient outcomes. Full article