The lack of energy conservation in brown adipose tissue mitochondria when prepared by conventional methods was established in the 1960s and was correlated with the thermogenic function of the tissue. In order to observe energy conservation, two requirements had to be met: the removal of the endogenous fatty acids and the addition of a purine nucleotide. These two factors have been the essential tools that led to the discovery of the energy dissipation pathway, the uncoupling protein UCP1. The activity is regulated by these two ligands. Purine nucleotides bind from the cytosolic side of the protein and inhibit transport. Fatty acids act as seconds messengers of noradrenaline and increase the proton conductance. This review presents a historical perspective of the steps that led to the discovery of UCP1, its regulation, and our current view on its mechanism of transport.