Understanding the molecular mechanisms that mediate the response of cells to mechanical stimuli, the process known as mechanotransduction, has emerged as a research topic with relevance to human health and disease. Mechanotransduction in bone is particularly relevant because the mammalian skeleton remodels to adapt to its loading environment The mechanosome hypothesis has been proposed to explain how mechanical signals detected at the bone cell membrane are converted into changes in transcription of target genes. In one model, adhesion complexes at the surface of the sensor cell activate multiprotein complexes (mechanosomes) that include both proteins involved in adhesion and transcription factors that move to the nucleus and regulate transcriptional activity of target genes. New work has identified a previously unknown mechanotransduction complex-consisting of nitric oxide (NO), cyclic guanosine monophosphate (cGMP), protein kinase G II, SHP-1, and SHP-2-that associates with β₃ integrins through Src. This complex regulates gene expression in response to fluid flow and has several of the necessary elements of a mechanosome complex. These findings beg the question of just how extensive the mechanosome network is and how mechanosomes interact with other signal transduction pathways that also respond to mechanical load.