Over the last decade, much effort has been devoted to unraveling the genetics of osteoporosis-related traits. Although progress has been slow, a number of significant advances have been made recently through the use of genome-wide association (GWA) approaches. Despite these successes, however, our understanding is still very incomplete. Global gene expression data are starting to be used to improve gene discovery and elucidate the mechanisms underling genetic associations. This Perspective focuses on these “systems genetics” approaches and how they are being used to complement and enhance genetic analyses and improve our understanding of osteoporosis. IBMS BoneKEy. 2010 October; 7 (10): 353-363.© 2010 International Bone & Mineral Society