Recent preclinical and clinical studies have unfolded the potential of pharmacological modulation of activities of sphingosine-1-phosphate (S1P) receptors and S1P metabolizing enzymes for the development of therapeutic interventions against a variety of pathologies. An understanding of differential and temporal effects of hypoxia exposure on the key components of S1P signalling would certainly aid in designing improved drug development strategies in this direction. In view of this, the aim of the present study was to assess the effect of progressive hypobaric hypoxia exposure on expression of S1P receptors (S1PR1-5) and specific activities of S1P synthesizing enzymes--neutral sphingomyelinase (nSMase) and sphingosine kinase (Sphk) in pulmonary and cerebral tissues of rats exposed to simulated altitude of 21,000 feet in an animal decompression chamber. Along with this, development of cerebral and pulmonary edema and markers of inflammation were studied at 12, 24, and 48 h to validate our study model of hypobaric hypoxia-induced stress. The protein expression of S1PR1-5 and activities of Sphk and nSMase enzymes were observed to be dramatically affected by simulated hypobaric hypoxia exposure, concurrent with deterioration of pathology, with 12 h of exposure appearing to be the most critical of the various time points studied.