The intrahepatic immune environment is associated with the induction of tolerance, yet maintains the capacity to sustain effective responses against pathogens. The mechanisms underlying this dichotomy are unclear. Recent data indicate that activation of naïve CD8(+) T cells occurs within the liver. However, in contrast to efficient primary activation observed within the lymph nodes, this pathway is relatively ineffective, leading to reduced CD8(+) T-cell cytotoxicity and survival. Thus, the outcome of intrahepatic CD8(+) T-cell responses might be determined by whether primary activation occurs within the tolerogenic environment of the liver, or whether immunity is induced by initial antigen encounter within the lymph nodes. These findings support a novel model of hepatic-immune interactions, with implications for our understanding of the paradoxical nature of liver immunobiology.