Protein stability is critical to the outcome of nearly all thermally mediated applications to biomaterials such as thermal therapies (including cryosurgery), burn injury, and biopreservation. As such, it is imperative to understand as much as possible about how a protein loses stability and to what extent we can control this through the thermal environment as well as through chemical or mechanical modification of the protein environment. This review presents an overview of protein stability in terms of denaturation due to temperature alteration (predominantly high and some low) and its modification by use of chemical additives, pH modification as well as modification of the mechanical environment (stress) of the proteins such as collagen. These modifiers are able to change the kinetics of protein denaturation during heating. While pH can affect the activation energy (or activation enthalpy) and the frequency factor (or activation entropy) of the denaturation kinetics, many other chemical and mechanical modifiers only affect the frequency factor (activation entropy). Often, the modification affecting activation entropy appears to be linked to the hydration of the protein. While the heat-induced denaturation of proteins is reasonably well understood, the heat denaturation of structural proteins (e.g., collagen) within whole tissues remains an area of active research. In addition, while some literature exists on protein denaturation during cold temperatures, relatively little is known about the kinetics of protein denaturation during both freezing and drying. Further understanding of this kinetics will have an important impact on applications ranging from preservation of biomaterials and pharmaceutics to cryosurgery. Interestingly, both freezing and drying involve drastic shifts in the hydration of the proteins. It is clear that understanding protein hydration at the molecular, cellular, and tissue level will be important to the future of this evolving area.