SPL inhibition is proposed as a strategy for raising S1P levels to inhibit lymphocyte trafficking and to promote cell survival in conditions causing tissue injury. Aldehyde depletion could be of potential benefit in Sjögren–Larsson syndrome. Potential risks include promotion of carcinogenesis, inhibition of innate immune functions, perturbation of lipid homeostasis, increased acute phase reactants. SPL delivery or upregulation is proposed as a strategy for depleting S1P in conditions such as cancer, fibrosis and pathologic angiogenesis, wherein monoclonal antibodies to S1P and sphingosine kinase inhibition have shown utility. Potential risks include sensitizing non-malignant cells to cytotoxic therapy and SPL product accumulation. Key determinants of safety and efficacy will likely include the degree of SPL inhibition or activation, the timing and duration of the intervention, and tissue specificity (as determined by the bioavailability and biodistribution of SPL modulating agents).