Mechanical loading provides an anabolic stimulus for bone. More importantly, the mechanosensing apparatus in bone directs osteogenesis to where it is most needed for improving bone strength. The biological processes involved in bone mechanotransduction are poorly understood and further investigation of the molecular mechanisms might uncover drug targets for osteoporosis. Several pathways are emerging from current research, including membrane ion channels, ATP signaling, and second messengers such as prostaglandins and nitric oxide. Some key molecular targets include the Ltype calcium channel (alpha 1C isoform), a gadolinium-sensitive stretch-activated channel, P2Y2 and P2X7 purinergic receptors, EP2 and EP4 prostanoid receptors, and the parathyroid hormone receptor. One characteristic of the mechanosensing apparatus that has only recently been studied is the important role of desensitization. Experimental protocols that insert “rest” periods to reduce the effects of desensitization can double anabolic responses to mechanical loading. A drug therapy that suppresses desensitization pathways may provide an effective means to build bone strength.