Mechanical loads are vital regulators of skeletal mass and architecture as evidenced by the increase in bone formation following the addition of exogenous loads and loss of bone mass following their removal. While our understanding of the molecular mechanisms by which bone cells perceive changes in their mechanical environment has increased rapidly in recent years, much remains to be learned. Here, we outline the effects of interstitial fluid flow, a potent biophysical signal induced by the deformation of skeletal tissue in response to applied loads, on bone cell behavior. We focus on the molecular mechanisms by which bone cells are hypothesized to perceive interstitial fluid flow, the cell signaling cascades activated by fluid flow, and the use of this signal in tissue engineering protocols.