Sphingosine phosphate lyase (SPL) is a pyridoxal 5’-phosphate-dependent intracellular enzyme that catalyzes the final step in the sphingolipid degradative pathway. It is responsible for the irreversible cleavage of the bioactive sphingolipid sphingosine-1-phosphate (S1P), yielding two products with biological functions of their own. SPL guards the only exit point of sphingolipid catabolism, and its dysfunction can lead to aberrant or disrupted S1P signaling and the accumulation of other cytotoxic upstream sphingolipid intermediates. The first SPL-encoding gene to be discovered was identified in a yeast genetic screen in 1997. Reverse genetics led to the identification of other genes in the pathway. Forward genetics led to the identification of SPL-encoding genes from other species, including the mouse and human SPL homologs, Sgpl1/SGPL1. Two decades later, a severe genetic condition—SPL insufficiency syndrome, or SPLIS—caused by recessive mutations in SGPL1 was recognized. Affected children exhibit renal failure, adrenal insufficiency, neuropathy, ichthyosis and immunodeficiency. There is no specific treatment or cure for SPLIS. We are exploring several therapeutic strategies for SPLIS, including cofactor supplementation, gene therapy and enzyme replacement therapy.