Obesity is a widely accepted risk factor for cardiovascular disease, as increased body mass index (BMI) has been associated not only with classic cardiovascular risk factors like type 2 diabetes mellitus, hypertension, and hyperlipidaemia but also with coronary artery disease, heart failure, atrial fibrillation, and stroke, independently of other risk factors. This was initially believed to be due to the detrimental effects of adipose tissue (AT)-derived molecules (e.g. adipokines) on the human arterial wall and heart. However, during the last decade, it has become clear that the association between obesity and cardiovascular disease is much more complex than originally anticipated. Epidemiological studies have shown a U-shaped relationship between BMI and survival, with higher short- and mid-term survival rates observed among overweight individuals (BMI 25–30 kg/m2), while ‘normal’ body weight (BMI 20–24.9 kg/m2) only related with better long-term survival (>15 years). This paradoxically ‘protective’ effect of obesity was more evident in individuals with chronic diseases, including heart failure, renal failure, or cancer. This ‘obesity paradox’ was originally explained by the inability of BMI to capture fat distribution in the body, since visceral obesity was felt to be particularly detrimental, while gluteal/subcutaneous fat has a neutral effect on cardiovascular risk prediction. Visceral obesity was therefore defined as metabolically unhealthy obesity, while gluteal obesity was defined as metabolically healthy obesity.5 However, the most important lesson to be learned from studying the ‘obesity paradox’ was that AT may actually sense systemic signals of cachexia related to chronic diseases, the latter would initiate lipolysis, a phenomenon driving weight loss in chronic conditions like cancer or heart failure, leading to misinterpretations of the relationship between body fat mass and survival. These considerations imply that AT can be used as a biosensor of the severity of chronic diseases, turning it into a potential source of diagnostic or prognostic biomarkers. Therefore, understanding the biological nature of the cross-talk between AT and the cardiovascular system is an unmet need, that will almost certainly lead to the discovery of new therapeutic targets and the development of novel diagnostic biomarkers in cardiovascular medicine.