Frozen and freeze-dried biotherapeutical products are exposed to various interfaces during manufacture and use. Three types of interfaces are considered in this chapter, i.e., air/solution, ice/solution, and interface between dried protein formulations and the gas phase. Air/solution interfaces, in the form of air bubbles, can be formed both during freezing as the result of expulsion of dissolved air by growing ice crystals and during reconstitution of lyophiles. Protein mols. have a tendency to accumulate at the air/solution interfaces, which could promote unfolding. Ice/solution interface, which protein mols. encounter during both freezing storage and freeze-drying, can destabilize protein either directly, if protein mols. are sorbed on ice crystals or indirectly, when proteins mols. are partitioned in a liquid layer next to growing ice crystals. In spray-dried and freeze-dried formulations, higher protein concentration near the solid surface was reported in many cases; these mols. are expected to be less stable against various degradation mechanisms than those located in the bulk. It is concluded that, while good long-term stability can be expected for many frozen and freeze-dried protein formulations, freezing and drying unit operations also exposes proteins to interfacial stress conditions that can lead to degradation