Adhesion molecules have traditionally been thought of simply as receptors that permit anchorage to other cells or to the underlying extracellular matrix (ECM). However, within the past decade it has become apparent that adhesion molecules such as integrins mediate critical cytosolic signaling events that have a dramatic impact upon cell proliferation, survival, and motility. Integrins act to regulate both physiologic and pathologic events, including complex processes such as angiogenesis, tumor growth, and metastasis. For these reasons, integrins have become attractive targets for drug development, and several effective integrin antagonists are now under clinical evaluation. In turn, the use of integrin-targeted reagents has provided additional mechanistic insights into the workings of the receptor. In particular, it has become apparent that integrins are "mechanosensory" receptors that operate in a context-dependent manner. While integrins that ligate substrate-immobilized ligands typically transduce positive signals into the cell, antagonized or unligated integrins promote negative signaling into the cell, leading to cell cycle arrest or apoptosis. Thus, integrins appear to fulfill a biosensor function, wherein they constantly interrogate the local ECM, and modulate cell behavior accordingly. These new roles that integrins play reinforce the choice of integrins as a therapeutic target, even as they lead us to reassess and optimize current clinical strategies.