Insulin resistance, of which the incidence is dramatically increasing in Western societies, is usually regarded as a pathological condition. However, arguments can be provided that insulin resistance may be a normal physiological mechanism to let cells and organs deal with the competition for various sources of energy, especially under circumstances of energy stress. Here we review four different hypotheses dealing with insulin resistance: the glucose-fatty acid cycle, the ER and oxidative stress response, the selfish brain, and the thrifty/not-so-thrifty genotype. Each hypothesis has a specific view on insulin resistance, but they also can complement each other. Combining the four hypotheses supports the view that physiological insulin resistance is indeed one of the adaptive regulation mechanisms, which has benefit for survival of the organism by restoring and maintaining the energy balance at the cellular and organism level. In principle insulin resistance seems to be a reversible physiological trait implying that there may be a specific mechanism to down-regulate insulin resistance once the energy balance is regained. The combined model also describes several ways, by which insulin resistance is promoted during prolonged increased energy supply. A better understanding of the complex background of physiological insulin resistance and of the nature of its regulatory mechanisms will be valuable for the treatment of pathological insulin resistance and type 2 diabetes. The present review may be helpful for this.