In the 1870's, Ludwig Boltzmann proposed a simple equation that was based on the notion of atoms and molecules and that defined the probability of finding a molecule in a given state. Several years later, the Boltzmann equation was developed and used to calculate the equilibrium potential of an ion species that is permeant through membrane channels and to describe conformational changes of biological molecules involved in different mechanisms including: open probability of ion channels, effect of molecular crowding on protein conformation, biochemical reactions and cell proliferation. The aim of this review is to trace the history of the developments of the Boltzmann equation that account for the behaviour of proteins involved in molecular biology and physiology.