The burden of life-long immunosuppressive medication must be overcome if progress is to be made in long-term outcomes following transplantation. The liver exhibits intrinsic tolerogenic properties that contribute to a unique propensity toward spontaneous acceptance when transplanted. Hence, a proportion of liver transplant recipients develop a state of immunotolerance and display persistently normal allograft function despite the discontinuation of immunosuppression. However, this phenomenon remains elusive for the majority of recipients. Investigations performed in experimental models of spontaneous liver allograft tolerance and in clinical cases of immunosuppression-free liver transplant acceptance have yielded mechanistic insights at the heart of recent strategies toward tolerance prediction and promotion. Results from recent clinical trials signal a shift in how liver allograft tolerance is viewed—not an elusive rarity of academic interest, but a potentially relevant clinical opportunity, which can be safely pursued if appropriately targeted.