Abstract: This lecture will describe my lab’s emerging interest in non-equilibrium systems. I will use peptide macrocycles as a way to showcase functionally rich molecules that suffer from a poor understanding of conformational preferences. Evidence supports what my lab calls the “butterfly effect.” It describes situations where a small change at a given position of the ring results in disproportional consequences at distal position(s). Until recently, the available data has not translated into what matters most – a metric that describes the response of a given system to perturbation. To tackle this issue, we have implemented the concept of the dominant rotor, which allows us to create two-well systems with controlled conformational behavior. To reach our objectives, we are now designing amino acids and other building blocks that offer varying degrees of control over rotors. The most exciting outcome of this work is our capability to detect, study, and isolate conformational isomers in the 1-10 kcal/mol energy range. Our work underscores that operations away from equilibrium offer a fascinating possibility to control complex molecules.