There is substantial evidence that the enzymes, sphingosine kinase 1 and 2, which catalyse the formation of the bioactive lipid sphingosine 1-phosphate, are involved in pathophysiological processes. In this chapter, we appraise the evidence that both enzymes are druggable and describe how isoform-specific inhibitors can be developed based on the plasticity of the sphingosine-binding site. This is contextualised with the effect of sphingosine kinase inhibitors in cancer, pulmonary hypertension, neurodegeneration, inflammation and sickling.