<p>This piece serves two purposes. Firstly, it aims to ascertain the extent to which the ‘principle of least action’ enables us to identify which of the potential pathways and trajectories leading to novel protein sequences have the highest evolutionary efficiency—in addition to examining how variations in factors such as protein robustness and folding rates (resulting from the inevitability of destabilizing mutations) could impact this important evolutionary process. Secondly, it seeks to elucidate how ‘epistasis’ may influence the identification of the most efficient evolutionary pathways and trajectories according to the principle of least action—as well as to determine whether the presence of ‘epistatic effects’ may stem from a yet unidentified epistatic force. The initial findings suggest that protein evolution—at a molecular level—may be more predictable than previously thought, as ‘epistasis’ and the ‘principle of least action’ collectively impose constraints on evolutionary paths and trajectories, and consequently, on protein evolvability. Thus, this work should advance our understanding of the main molecular mechanisms that underlie the evolution of mutation-driven proteins and also provide grounds to answer a fundamental evolutionary question: how does Darwinian selection regard all potential trajectories available?</p>