Sphingolipids are not only essential components of cellular membranes but also function as intracellular and extracellular mediators that regulate important physiological cellular processes including cell survival, proliferation, apoptosis, differentiation, migration and immune responses. The liver possesses the unique ability to regenerate after injury in a complex manner that involves numerous mediators, including sphingolipids such as ceramide and sphingosine 1-phosphate. Here we present the current understanding of the involvement of the sphingolipid pathway and the role this pathway plays in regulating liver injury, repair and regeneration. The regulation of sphingolipids and their enzymes may have a great impact in the development of novel therapeutic modalities for a variety of liver injuries and diseases.