The objectives of the present study were (i) to assess the contribution of SphK1/S1P signaling in regulating HIF-1α expression under hypoxia in various osteosarcoma cell models, (ii) quantify SphK1 enzymatic activity in biopsies of osteosarcoma, and (iii) examine the relationship between SphK1, S1P receptor 1 (S1P1) and hypoxia (GLUT-1) in 130 cases of osteosarcoma by immunohistochemistry. The gene discussed is S1PR1; the disease is osteosarcoma.