Genes involved in HDL structure and metabolism have been overexpressed through the introduction of transgenes or inactivated by gene targeting in mice. These new experimental substrates make it possible to address hypotheses relevant to the biology of HDL that were previously inaccessible through human studies. The in-vivo studies performed to date with these engineered mice have provided insight into structural determinants of HDL, uncovered interactions between proteins that act on HDL and clarified the role that HDL-associated proteins play in atherosclerosis. Further use of these animals, coupled with the development of new engineered lines of mice, should help unravel many questions associated with the in-vivo biological properties and metabolism of HDL.