The contrasting actions of mechanical forces and glucocorticoids (GC) on bone have been long recognized. However, the cellular and molecular mechanisms by which these stimuli impact the skeleton remain only partially known. Recent evidence gained from studies on bone cell apoptosis has revealed that mechanical forces and GC exhibit converse effects on osteocyte and osteoblast survival resulting from divergent actions on the focal adhesion kinases FAK and Pyk2, molecules that regulate integrin-dependent interactions between bone cells and the extracellular matrix (ECM). This prospect reviews these findings and poses the possibility that similar opposing effects on kinase signaling are responsible for other actions of mechanical forces and GC on the skeleton, in particular on bone formation and the Wnt signaling pathway. J. Cell. Biochem. 111: 1–6, 2010. © 2010 Wiley-Liss, Inc.