Molecular studies of cold and frozen systems “be they naturally cold-hardy animals, cryopreserved cells/tissues/organs, or tissues ablated by cryosurgery” all have one thing in common. This is a need to identify and quantify biochemical markers of stress, injury and survival. Physical assessment methods (cell rupture, enzyme leakage, etc.) have long been used as have “bulk” protective strategies (e.g. cryoprotectant infusion). However, in-depth knowledge of the key biochemical parameters of cell systems under freezing stress, the negative versus positive responses that can constitute molecular markers of stress versus endurance, and the features that differentiate natural versus man-made freezing survival still leave much to be determined. Assessing complex cell functions has traditionally been difficult and time consuming absorbing many grad student careers for energy-intensive methods like gene screening, PCR, immunoblotting and enzyme assay. However, new technologies have recently emerged that are re-focusing research efforts and allowing huge amounts of data to be gathered from very small cell/tissue samples. Among these, accelerated rates of genome sequencing are giving us access to genomic tools to find inherent differences in genes between species and tools for screening a stress-responsive transcriptome (e.g. RNA seq.; the RT2 profiler array technology) or proteome are becoming easier and cheaper. This is providing ways to identify signatures of cells/organisms under stress. A relatively new analytical tool, multiplex suspension array technology (Luminex), is also radically changing biomedical analytical capabilities for both research and diagnostic purposes by providing a way to quantify panels of multiple analytes simultaneously in single small samples in a very short time. For example, this approach can allow multiple members of integrated signal transduction pathways to be quantified in a single sample. Critical assessments of metabolic status can also be derived from analyzing the patterns of posttranslational modification of macromolecules including the phosphoproteome or the epigenome. Quick ‘snapshots’ of transcriptional and translational control using state-of-the-art methodologies can identify derangements as varied as changes in cell cycle control, the status of apoptosis and autophagy, or microRNA involvement in stress and adaptation. Most of these technologies are now available in kit formats (that can often be customized) to screen for large numbers of targets simultaneously at an ever-decreasing cost to researchers. To illustrate the power of these new methodologies, a variety of examples of their use by my lab in probing the molecular adaptations for low temperature function in hibernating mammals, freeze tolerant frogs, and freeze/anoxia tolerant intertidal snails will be provided. For comparative and cryo-biochemistry the future is bright as we now have the capacity to apply the latest molecular technologies to analyze stress and adaptation.