During the last forty years, researchers have had the working hypothesis that genes upregulated by low temperatures protect plants from cold stress. When cDNA cloning technologies were developed about twenty years ago, cold-responsive genes such as genes for CBF/DREB transcription factors could be identified in Arabidopsis. The next step was to use microarray technologies to identify cold-regulated genes as a way to improve our understanding of cold tolerance. Unfortunately, there have been several problems with this approach; 1) upregulation of mRNA levels is only one of many mechanisms for the control of gene expression in plants, 2) published microarray results have not always been repeatable by other labs, 3) there has been a heavy emphasis on cold-regulated transcription factor genes to the exclusion of other important determinants, 4) the cold treatments used in several laboratory studies have not always been comparable to natural stress conditions and 5) there has often been a lack of follow-up research, using mutants to prove through functional genomics that specific genes are actually involved in cold tolerance. An alternative transcriptomic approach to identify genes for cold tolerance is chemical genetics based on glycine betaine treatments, using transcriptomics followed by functional studies with mutants. This approach was validated first for the RabA4c GTPase involved in membrane trafficking and has also identified a bZIP transcription factor and FRO2 ferric reductase. In conclusion, although transcriptomics has identified some determinants of cold stress tolerance, there still exists large gaps in our knowledge of this important process.