Sphingosine kinases (SphKs) are lipid kinases that catalyze the phosphorylation of sphingosine (Sph) to sphingosine-1-phosphate (S1P). As a bioactive lipid, S1P plays a role outside and inside the cell to regulate biological processes. The overexpression of SphKs is related to a variety of pathophysiological conditions. Targeting the S1P signaling pathway is a potential treatment strategy for many diseases. SphKs are key kinases of the S1P signaling pathway. The SphK family includes two isoforms: SphK1 and SphK2. Determination of the co-crystal structure of SphK1 with various inhibitors has laid a solid foundation for the development of small molecule inhibitors targeting SphKs. This paper reviews the differences and connections between the two isoforms and the structure of SphK1 crystals, especially the structure of its Sph "J-shaped" channel binding site. This review also summarizes the recent development of SphK1 and SphK2 selective inhibitors and the exploration of the unresolved SphK2 structure.