The pathophysiology of hepatic ischemia/reperfusion injury (IRI) includes a number of complex and diverse mechanisms involving interactions between hepatocytes, Kupffer cells, neutrophils, macrophages, sinusoidal endothelial cells, and platelets. Tumor Necrosis Factor-α (TNF-α), a cytokine produced by numerous cell types in response to inflammatory stimuli, is a well-known mediator during ischemia/reperfusion (IR) that plays a central role in injury to hepatocytes. TNF-α has a multifactorial effect in hepatic IRI because of the many interactions between TNF-α and reactive oxygen species, nitric oxide, adhesion molecules, and various cytokines and chemokines. The intracellular cascades that TNF-α triggers and their downstream effects are clearly presented throughout this manuscript. With these mechanisms in mind, ischemic preconditioning and pharmacological interventions with potential clinical application to prevent or attenuate IRI will be emphasized.