Santalum album L. (Indian sandalwood)is an economically important plant species because of its ability to produce highly valued perfume oils. Little is known about the mechanisms by which S. album adapts to low temperatures. In this study, we obtained 100,445,724 raw reads by paired-end sequencing from S. album leaves. Physiological and transcriptomic changes in sandalwood seedlings exposed to 4 °C for 0-48 h were characterized. Cold stress induced the accumulation of malondialdehyde, proline and soluble carbohydrates, and increased the levels of antioxidants. A total of 4,424 differentially expressed genes were responsive to cold, including 3,075 cold-induced and 1,349 cold-repressed genes. When cold stress was prolonged, there was an increase in the expression of cold-responsive genes coding for transporters, responses to stimuli and stress, regulation of defense response, as well as genes related to signal transduction of all phytohormones. Candidate genes in the terpenoid biosynthetic pathway were identified, eight of which were significantly involved in the cold stress response. Gene expression analyses using qRT-PCR showed a peak in the accumulation of SaCBF2 to 4, 50-fold more than control leaves and roots following 12 h and 24 h of cold stress, respectively. The CBF-dependent pathway may play a crucial role in increasing cold tolerance.Low temperature is one of the major abiotic factors that impedes plant growth and limits crop yield and geographical distribution The mechanism of cold stress in plants has been extensively studied over the last 20 years but the complete mechanisms by which plants perceive low temperatures still remain unknown. Research has shown that cold stress tolerance involves the remodeling of cell structures and reprogramming gene expression by triggering a series of protective mechanisms against cold damage, including an increase in the level of intracellular solutes, the accumulation of cryoprotectants and antioxidants, as well as the induction of antifreeze proteins and cold-regulated (COR) proteins 8,9 . During cold stress, these metabolites and proteins help to protect plant membranes and prevent cell disruption by stabilizing membrane lipids, maintaining ion homeostasis and scavenging reactive oxygen species (ROS) 3 . The molecular mechanisms underlying cold stress tolerance have been investigated in the model plant Arabidopsis, as well as in other crop species such as maize, wheat and barley 1,10,11 . Plants have developed C-repeat