Transgenic and knockout mice have proven invaluable tools for analyzing physiologically relevant functions of numerous genes. In some cases, however, pleiotropic effects that result from a variable requirement for a particular gene in different tissues, cell types, or stages of embryonic development may complicate the analysis due to a complex phenotype or embryonic lethality. The loxP/Cre-mediated recombination system, which allows tissue-specific gene targeting in the mouse, can be used to overcome these problems. A limitation of current methods is that a mouse carrying a loxP-tagged gene must be crossed with a transgenic mouse expressing the Cre recombinase in an appropriate tissue to obtain the desired gene rearrangement. We have used recombinant adenovirus carrying the Cre recombinase to induce virtually quantitative somatic cell gene disruption in the liver. The targeted gene was the multifunctional low-density lipoprotein receptor-related protein (LRP), a cell surface receptor for α2-macroglobulin and other ligands. Transient expression of Cre following adenoviral infection produced the predicted gene rearrangement, functionally inactivating LRP in the liver. Rearrangement occurred within 6 days after infection and remained stable for at least 28 days. The results demonstrate the suitability of adenoviral Cre gene transfer to induce long-term, quantitative, and temporally controlled gene disruption in the mouse.