Bone, a calcified tissue composed of 60% inorganic component (hydroxyapatite), 10% water and 30% organic component (proteins), has three functions: providing mechanical support for locomotion, protecting vital organs, and regulating mineral homeostasis. A lifelong execution of these functions depends on a healthy skeleton, which is maintained by constant bone remodeling in which old bone is removed by the bone-resorbing cell, osteoclasts, and then0 replaced by new bone formed by the bone-forming cell, osteoblasts. This remodeling process requires a physical interaction of bone with these bone cells. Moreover, numerous cancers including breast and prostate have a high tendency to metastasize to bone, which is in part attributable to the capacity of the tumor cells to attach to bone. The intensive investigation in the past two decades has led to the notion that the cell-bone interaction involves integrins on cell surface and bone matrix proteins. However, the biochemical composition of bone and emerging evidence are inconsistent with this belief. In this review, I will discuss the current understanding of the molecular mechanism underlying the cell-bone interaction. I will also highlight the facts and new findings supporting that the inorganic, rather than the organic, component of bone is likely responsible for cellular attachment. © 2009 Bentham Science Publishers Ltd.