The global prevalence of obesity and overweight were 16% and 43% in 2022 according to the Wold Health Organization. The rise in these numbers increases the risk of many diseases including diabetes, heart disease, dementia, and cancer. The systemic and physiological causes of obesity are multi-level and multi-factorial, and may differ between individuals. In this lecture, evidence will be reviewed from human studies and animal models supporting the concept that hyperinsulinemia is a key causal driver in the development of obesity. Physiological mechanisms will be addressed. Potential interventions will be discussed, as well as the potential requirement for individualized approaches to match the physiology of the patient. The limitations of our current knowledge, as well as a roadmap for future studies will be discussed.