Artificial intelligence (AI) has the potential to transform every facet of cardiovascular practice and research. The exponential rise in technology powered by AI is defining new frontiers in cardiovascular care, with innovations that span novel diagnostic modalities, new digital native biomarkers of disease, and high-performing tools evaluating care quality and prognosticating clinical outcomes. These digital innovations promise expanded access to cardiovascular screening and monitoring, especially among those without access to high-quality, specialized care historically. Moreover, AI is propelling biological and clinical discoveries that will make future cardiovascular care more personalized, precise, and effective. The review brings together these diverse AI innovations, highlighting developments in multimodal cardiovascular AI across clinical practice and biomedical discovery, and envisioning this new future backed by contemporary science and emerging discoveries. Finally, we define the critical path and the safeguards essential to realizing this AI-enabled future that helps achieve optimal cardiovascular health and outcomes for all., Competing Interests: Funding Support and Author Disclosures This work was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health (under awards R01HL167858 and K23HL153775 to Dr Khera, F32HL170592 to Dr Oikonomou, R01HL155915 and R01HL167050 to Dr Nadkarni, R01HL158626 to Dr Wiens, and UM1 TR004407 to Dr Topol). Dr Khera is an Associate Editor of JAMA; receives research support, through Yale, from the Blavatnik Foundation, Bristol Myers Squibb, Novo Nordisk, and BridgeBio; is a coinventor of U.S. Provisional Patent Applications 63/177,117, 63/428,569, 63/346,610, 63/484,426, 63/508,315, 63/580,137, 63/606,203, 63/562,335; and is a co-founder of Ensight-AI, Inc and Evidence2Health, LLC. Dr Oikonomou is an academic cofounder of Evidence2Health LLC; has been a consultant for Caristo Diagnostics, Ltd and Ensight-AI, Inc; is a co-inventor in patent applications (US17/720,068, 63/619,241, 63/177,117, 63/580,137, 63/606,203, 63/562,335, WO2018078395A1, WO2020058713A1); and has received royalty fees from technology licensed through the University of Oxford. Dr Nadkarni is an academic cofounder of Renalytix, Pensieve, and Data2Wisdom; has patents licensed to Heart Test Laboratories; and acts as a consultant to Renalytix, Pensieve, and Heart Test Laboratories. Dr Butte is a cofounder and consultant to Personalis and NuMedii; has served as a consultant or advisor to National Institutes of Health, JAMA, Mango Tree Corporation, Samsung, Geisinger Health, Washington University in Saint Louis, University of Utah, and in the recent past, 10x Genomics, Helix, Pathway Genomics, and Verinata (Illumina); has served on paid advisory panels or boards for Regenstrief Institute, Gerson Lehman Group, AlphaSights, Covance, Novartis, Genentech, Merck, and Roche; is a shareholder in Personalis and NuMedii; is a minor shareholder in Apple, Meta (Facebook), Alphabet (Google), Microsoft, Amazon, NVIDIA, AMD, Snap, 10x Genomics, Doximity, Regeneron, Sanofi, Pfizer, Royalty Pharma, Moderna, BioNtech, Invitae, Pacific Biosciences, Editas Medicine, Eli Lilly, Nuna Health, Assay Depot (Scientist.com), Vet24seven, Snowflake, Sophia Genetics, and several other nonhealth-related companies and mutual funds; has received honoraria and travel reimbursement for invited talks from Johnson and Johnson, Roche, Genentech, Pfizer, Merck, Lilly, Takeda, Varian, Mars, Siemens, Optum, Abbott, Celgene, AstraZeneca, AbbVie, Westat, Applied Research Works, Acentrus, ALDA, and many academic institutions, medical- or disease-specific foundations and associations, and health systems; has received royalty payments through Stanford University, for several patents and other disclosures licensed to NuMedii and Personalis; and his research has been funded by the National Institutes of Health, U.S. Food and Drug Administration, Peraton (as the prime on an National Institutes of Health contract), Priscilla Chan and Mark Zuckerberg, the Barbara and Gerson Bakar Foundation, Genentech, Johnson and Johnson, Chan Zuckerberg Science, Robert Wood Johnson Foundation, Leon Lowenstein Foundation, Intervalien Foundation, and in the past, the March of Dimes, Juvenile Diabetes Research Foundation, California Governor’s Office of Planning and Research, California Institute for Regenerative Medicine, L’Oreal, and Progenity (none of these entities had any role in the design, planning, or execution of the study, or interpretation of the findings). Dr Topol is on the scientific advisory board of Tempus, Abridge, and Pheno.ai. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)