Werner syndrome (WS) is a rare autosomal recessive genetic instability/cancer predisposition disorder that displays many symptoms of premature aging. The mimicry of agerelated phenotypes in WS, as well as its dependence on a single defective gene product, has provided the impetus for studying this fascinating disease as a model system for normative aging and its related pathologies such as atherosclerosis, neoplasia, diabetes mellitus, and osteoporosis. The gene product defective in WS, WRN, is a member of the RecQ DNA helicase family that is widely distributed in all kingdoms of life, and is believed to play a central role in genomic stability by preferentially operating on non-canonical DNA structures. Although there have been considerable advances in our understanding of the biochemistry of WRN and its interacting protein partners, the in vivo molecular function(s) of WRN remain(s) elusive. In addition to summarizing the features and clinical progression of WS, the following chapter details our current understanding of the WRN protein with respect to its biochemistry and its interacting protein partners, and considers its putative in vivo roles in various DNA transactions.