Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that plays a critical role in regulating various physiological and pathophysiological processes, including cancer, atherosclerosis, diabetes, and osteoporosis. S1P is produced by sphingosine kinase isoenzymes (SphK1 and SphK2) and acts through five specific G protein-coupled receptors (S1PR1-5). S1P has both extracellular and intracellular functions. Extracellularly, S1P acts through S1PRs to regulate cell trafficking, vascular tone, and permeability. Intracellularly, S1P counteracts apoptosis, modulates gene transcription, and interacts with proteins such as histone deacetylases, TRAF2, PKCδ, PHB2, and BACE1. In diseases, S1P is implicated in cancer growth, resistance to apoptosis, angiogenesis, and metastasis. In atherosclerosis, S1P regulates vascular tone, monocyte migration, and smooth muscle cell proliferation. In diabetes, S1P is involved in insulin resistance and ceramide production. In osteoporosis, S1P regulates osteoclast and osteoblast functions. The development of S1P-specific inhibitors and agonists has shown promise in treating these diseases, highlighting the potential of targeting S1P signaling for therapeutic intervention.Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite that plays a critical role in regulating various physiological and pathophysiological processes, including cancer, atherosclerosis, diabetes, and osteoporosis. S1P is produced by sphingosine kinase isoenzymes (SphK1 and SphK2) and acts through five specific G protein-coupled receptors (S1PR1-5). S1P has both extracellular and intracellular functions. Extracellularly, S1P acts through S1PRs to regulate cell trafficking, vascular tone, and permeability. Intracellularly, S1P counteracts apoptosis, modulates gene transcription, and interacts with proteins such as histone deacetylases, TRAF2, PKCδ, PHB2, and BACE1. In diseases, S1P is implicated in cancer growth, resistance to apoptosis, angiogenesis, and metastasis. In atherosclerosis, S1P regulates vascular tone, monocyte migration, and smooth muscle cell proliferation. In diabetes, S1P is involved in insulin resistance and ceramide production. In osteoporosis, S1P regulates osteoclast and osteoblast functions. The development of S1P-specific inhibitors and agonists has shown promise in treating these diseases, highlighting the potential of targeting S1P signaling for therapeutic intervention.