The use of animals lacking genes or expressing genes under the control of cell-specific promoters has significantly increased our knowledge of the genetic and molecular basis of physiopathology, allowing testing of functional hypotheses and validation of biochemical and pharmacologic approaches in order to understand cell function. However, with unexpected frequency, gene knockout animals and, more commonly, animal models of transgenesis give experimental support to even opposite conclusions on gene function. Here we summarize what we learned on the role of cyclooxygenase 2 (COX-2) in liver and revise the results obtained (COX-2) in liver and revise the results obtained in 3 independent models of mice expressing a COX-2 transgene specifically in the hepatocyte. Upon challenge with pro-inflammatory stimuli, the animals behave very differently, some transgenic models having a protective effect but others enhancing the injury. In addition, one transgene exerts differential effects on normal liver physiology depending on the transgenic animal model used.