Inflammatory bowel disease is associated with an increased risk of colorectal cancer. Colitis-associated cancer is a classical inflammation-driven cancer in which constitutive NFκB and STAT3 activation drive tumorigenesis. Recent findings published by Liang et al. in Cancer Cell demonstrate that sphingosine kinase 1 (SphK1)-mediated upregulation of sphingosine-1-phosphate (S1P) drives a persistent NFκB/IL-6/STAT3/sphingosine-1-phosphate receptor 1 (S1PR1) amplification loop that is critical to the development of chronic colitis and colitis-associated cancer. FTY720, an antagonist of S1PR1, abolished persistent NFκB/IL-6/STAT3 signaling and reduced the development and progression of colitis-associated cancer. Targeting SphK1/S1P/S1PR1 may provide a therapeutic option to prevent the progression of colitis to cancer.