It is well known that decreased temperature results in the suppression of metabolic activity and, thus, in a reduction of the rate at which deterioration of an unnourished biological system would occur. The freezing process, however, is not necessarily benign; it generally induces extreme variations in chemical, thermal, and electrical properties that could be expected to alter cellular membranes, intracellular organelles, and the associated delicate intracellular system functions. Given the extreme complexity of even the simplest biological cells, it is therefore remarkable that a reversible state of suspended animation by freezing is possible at all. Biological responses to cold stress can include (among others) disassembly of cell cytoskeleton, apoptosis, osmotic stress, oxidative stress and attenuation of transcription and translation. As a result, surviving post thawed cells may not function immediately as they did before, or may have been completely compromised. As deeper understanding of the molecular mechanisms has been uncovered, issues affecting the transcriptome due to cold stress have become identifiable as areas requiring attention. While the goal of any preservation strategy should be geared towards outcomes with no change to the cell or biological system (e.g. tissue or organ) pre-preservation, the ability to repair cells post preservation could mitigate inevitable compromises. Additionally, arbitrary “viability” counts generally accepted by various regulatory bodies need to be examined from the standpoint of evidence. Historically, some situations, such as autologous peripheral blood hematopoietic stem cell transplantation, have required higher doses of cells with lower viability due to the nature of preserving that system. Outcomes from these transplants can still yield good results in vivo. Preservation protocols that combine optimized preservation, “adjuvants” and factors that can provide support in vivo might be key to solving the very complex situations in organ preservation and importantly, use.