The article reviews the role of perilipins (Plins) in oxidative stress and their implications for cardiovascular disease. Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, is a common factor in myocardial diseases, including heart failure, cardiac ischemia-reperfusion injury, hypertrophy, and diabetic cardiomyopathy. Lipid droplets (LDs), which are coated with Plins, play a crucial role in alleviating cellular stress, particularly oxidative stress. The review highlights the interplay between LDs, Plins, and oxidative stress, emphasizing the protective functions of Plins in managing ROS levels and preventing cardiac dysfunction. Key findings include the upregulation of Plin2 and Plin5 in response to oxidative stress, their roles in reducing ROS production, and their potential as therapeutic targets for cardiovascular diseases. The article also discusses the transcriptional and posttranslational regulation of Plins by ROS and the challenges in modulating Plin levels for therapeutic intervention. Overall, the review underscores the importance of Plins in maintaining cardiac health and their potential as therapeutic agents in addressing oxidative stress-related cardiac diseases.The article reviews the role of perilipins (Plins) in oxidative stress and their implications for cardiovascular disease. Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, is a common factor in myocardial diseases, including heart failure, cardiac ischemia-reperfusion injury, hypertrophy, and diabetic cardiomyopathy. Lipid droplets (LDs), which are coated with Plins, play a crucial role in alleviating cellular stress, particularly oxidative stress. The review highlights the interplay between LDs, Plins, and oxidative stress, emphasizing the protective functions of Plins in managing ROS levels and preventing cardiac dysfunction. Key findings include the upregulation of Plin2 and Plin5 in response to oxidative stress, their roles in reducing ROS production, and their potential as therapeutic targets for cardiovascular diseases. The article also discusses the transcriptional and posttranslational regulation of Plins by ROS and the challenges in modulating Plin levels for therapeutic intervention. Overall, the review underscores the importance of Plins in maintaining cardiac health and their potential as therapeutic agents in addressing oxidative stress-related cardiac diseases.