This chapter discusses simulated annealing-optimal histogram applications to the protein-folding problem. The basic idea that proteins could be reconstituted or refolded under the appropriate conditions was further validated by Privalov, and it forms the basis of the thermodynamic hypothesis of protein folding. Convergence in thermodynamic averages can be quite slow in simulations of this type greatly affecting our ability to reliably calculate key parameters, such as specific heat, for the folding process. This is true of many applications of simulated annealing in chemistry and physics. Multiple annealing simulations will also be analyzed using order parameters to further investigate the thermodynamic reversibility of the process, allowing any glassy behavior in the system to be identified if present. As the system cools, the value and variance of the overlap function provides a measure of the uniqueness of the conformer, as well as evidence to support the existence of potential phase transitions.