Dyslipidemia and insulin resistance predispose individuals to development of obesity, diabetes, cancer, myocardial infarction and stroke. A large body of evidence suggests that a class of toxic lipids, termed ceramides that is induced during inflammation and obesity, contribute to these metabolic impairments and the ensuing development of these cardiovascular disorders. In mice, blocking ceramide production improves insulin sensitivity, resolves hepatic steatosis and hypertriglyceridemia, and prevents atherosclerosis and heart failure. We recently found that ceramides serve as signals of nutrient excess that alter the metabolic activity of mature adipocytes—and thus the entire organism. Our research program aims to understand how ceramides impair nutrient sensing in adipose tissue and contribute to development of metabolic diseases such as obesity, diabetes, cardiovascular diseases etc. We will address this question using an array of “omics”, genetics, cellular and molecular biology techniques, and mouse physiology with the aim to identify novel ceramide-regulated factors that regulate adipose tissue function. We believe, determination of the roles of these novel effectors of ceramide action will enable us to identify novel therapeutic targets to combat cardiometabolic disease.