Insulin resistance is a complex pathological condition that can be defined as the state in which insulin levels, effective in normal subjects, do not produce their known biological effects, especially at the level of adipose tissue, muscle tissue, and liver. Insulin resistance is one of the central mechanisms involved in the emergence of the constellation of chronic diseases united under the name of cardiovascular-kidney-metabolic syndrome. Obesity, a chronic disease characterized by the accumulation of excess and/or dysfunctional adipose tissue, the accumulation of ectopic adipose tissue, represents the turning point in the development of insulin resistance, with consequences at the metabolic, cardiovascular, renal, and hepatic levels. In this context, the implementation of strategies to combat insulin resistance constitutes a central element in the therapeutic approach of cardiovascular-kidney-metabolic syndrome.