Obesity has reached epidemic proportions and complications related to obesity contribute substantially to both healthcare costs and mortality. Obesity, particularly when accompanied by an excess of visceral/ectopic fat, is a major risk factor for diseases ranging from insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, and cardiovascular disease. The epidemic proportions reached by obesity has made these conditions a global problem in human health. Accordingly, preventive and/or therapeutic interventions should be considered in obese patients. Regular physical activity/exercise has numerous beneficial effects on the cardiometabolic risk profile and on the cardiovascular system. However, our current clinical environment is not designed to provide the regular support needed by patients to help them maintain over the long term their improved physical activity/nutritional habits. Because hypertension, dyslipidemia, hyperinsulinemia, and excess visceral adipose tissue are linked by complex reciprocal molecular interactions, it is logical to expect that targeting an interconnected pathway may provide multiple benefits. At this stage, combined therapy of statins or PPAR agonists and renin-angiotensin-aldosterone system blockers to target multiple therapeutic pathways may optimally improve the cardiometabolic risk profile through both distinct and interrelated mechanisms. In the present article, we will discuss updated novel approaches, including potential multi-targeted intervention strategies, based on underlying pathophysiological processes.