Sandalwood oil is an essential oil obtained from the tree wood of various species of Santalum spp by steam distillation, and has a history of medicinal use besides as a fragrance. However the mechanisms involved in its activity are still unclear. In the present report, Sandalwood oil (S. album) was applied to living human skin explants to evaluate the sustained activity of the oil through gene expression profiling. Transcriptomic analysis showed a number of metabolic pathways and biological activities triggered by treatments previously described for aloe, curcumin and luteolin. No inflammatory responses accompanied the beneficial activities. The most intriguing impact was the natural effect on the retinoic acid (vitamin A) metabolism. Furthermore, we found that mechanisms normally acting in more specialized cell types such as immune cells, adipocytes, nerve cells, or hair follicles were activated in human skin explants in response to sandalwood oil. Thus, the oil may have the potential of further beneficial activities such as its antibacterial activity among other protective mechanisms. These results corroborate at a molecular level the rationale for clinical studies with sandalwood oil and support recent studies of patients with eczema (atopic dermatitis) or acne, which is often accompanied by bacterial growth on skin of Propionibacterium acnes.