By controlling sphingosine 1-phosphate (S1P) catabolism, S1P lyase (SPL) represents an undeniable candidate as potential regulator of a cancer cell's fate in response to stress. Our recent study reveals that complete loss of SPL activity leads to upregulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL and consequently protects against apoptosis induced by chemotherapy and nutrient starvation but not against autophagy. Here, we speculate on how S1P and disruption of S1P breakdown may regulate cell death and autophagy.