The field of cryopreservation has a long and successful history of in-depth study and progress. Advances in our knowledge base and our ability to cryopreserve cells have been consequential and have led to its widespread integration into academic, clinical, and agricultural settings. While many cell systems are successfully cryopreserved today, there remains significant cell loss associated with cryopreservation. Moreover, even today some cell systems remain uncryopreservable from a practical perspective. This is due to the diversity of post-freeze responses of individual cells to the various stressors experienced during the freeze-thaw process. In 1998, several independent groups reported on the direct involvement of apoptotic and necrotic cell death following cryopreservation (Baust, et al., 1998 and Borderie, et al., 1998). In addition to those reports, a substantial literature base describing the modulation of cell death through the use of various protease inhibitors, free radical scavengers, media formulations, and other novel compounds exist. These studies have identified diverse molecular-based, cellular responses to cryopreservation and have further demonstrated the significant improvements in cell survival through the modulation of molecular events. Numerous studies have reported on the molecular-based phenomena of cryopreservation-induced delayed onset cell death, yet our understanding of the pathway activation, progression, control, and the downstream effect on cell function remains in its infancy. To this end, modulation studies, such as targeted apoptotic control (TAC), have shown promise in furthering our understanding of the activation pathways and are proving to be a critical next step in the evolution of the cryopreservation sciences. This review provides an overview of the current literature on the mechanisms of cell death associated with cryopreservation failure.