For the past 40 years, the methodology for stress echocardiography (SE) has remained basically unchanged. It is based on two-dimensional, black and white imaging, and is used to detect regional wall motion abnormalities (RWMA) in patients with known or suspected coronary artery disease (CAD). In the last five years much has changed and RWMA is not enough on its own to stratify patient risk and dictate therapy. Patients arriving at SE labs often have comorbidities and are undergoing full anti-ischemic therapy. The SE positivity rate based on RWMA fell from 70% in the eighties to 10% in the last decade. The understanding of CAD pathophysiology has shifted from a regional hydraulic disease to a systemic biologic disease. The conventional view of CAD encouraged the use of coronary anatomic imaging for diagnosis and the oculo-stenotic reflex for the deployment of therapy. This has led to a clinical oversimplification that ignores the lessons of pathophysiology and epidemiology, and in fact, CAD is not synonymous with ischemic heart disease. Patients with CAD may also have other vulnerabilities such as coronary plaque (step A of ABCDE-SE), alveolar-capillary membrane and pulmonary congestion (step B), preload and contractile reserve (step C), coronary microcirculation (step D) and cardiac autonomic balance (step E). The SE methodology based on two-dimensional echocardiography is now integrated with lung ultrasound (step B for B-lines), volumetric echocardiography (step C), color-and pulsed-wave Doppler (step D) and non-imaging electrocardiogram-based heart rate assessment (step E). In addition, qualitative assessment based on the naked eye has now become more quantitative, has been improved by contrast and based on cardiac strain and artificial intelligence. ABCDE-SE is now ready for large scale multicenter testing in the SE2030 study.