Recent research on the effectiveness of training interventions indicates major alterations of hepatic lipid metabolism and suggests a substantial and beneficial adaptation of the liver to regular physical activity in humans. However, while various' data demonstrate the response of the working skeletal muscle to acute exercise and training, considerably less is known about the molecular events in the liver during and after increased physical activity. Here we discuss recent studies performed in rodents, that elucidate the acute hepatic response to one single bout of exercise with particular emphasis on stress response-related pathways. The acute transcriptional response to one exercise bout comprises three-times more hepatic transcripts than those expressed in soleus muscle, with a significantly more pronounced up- or downregulation of hepatic genes. Evaluation of the affected pathways shows that the liver responds to acute exercise with a rapid activation of the mitogen-activated protein kinase (MAPK) signalling pathway, of the p53 protein, and of interleukin (IL)-6-type cytokine signalling pathways, resulting in a marked transcriptional upregulation of stress response genes (e.g., transcription factors of the Fos/Jun-family, growth arrest and DNA damage (GADD)45gamma, and p53-target genes) and genes typically induced by energy depletion, e.g., insulin-like growth factor binding protein (IGFBP)-1, peroxisome proliferator-activated receptor coactivator (PGC)1alpha. One explanation for the marked differential expression of hepatic genes immediately after exercise is the induction of energetic stress. After non-exhaustive exercise energy depletion predominantly occurs in the liver not as much in the working muscle, and during exercise, the liver is exposed to altered concentrations of insulin and glucagon in the portal vein. Furthermore, lower plasma glucose levels post-exercise are related to increased expression levels of stress response genes. It appears that the unique function of the liver to supply glucose for the working muscle renders this organ especially susceptible for exercise-induced cellular stress that leads to the marked induction of defense adaptations. These results give rise to the question whether these molecular events are linked not only to stress defense but to the metabolic adaptations of the liver to exercise.