Current knowledge of molecular signaling during craniofacial development is advancing rapidly. We know that cells can respond to mechanical stimuli by biochemical signaling. Thus, the link between mechanical stimuli and gene expression has become a new and important area of the morphological sciences. This field of research seems to be a revival of the old approach of developmental mechanics, which goes back to the embryologists His (1874), Carey (1920), and Blechschmidt (1948). These researchers argued that forces play a fundamental role in tissue differentiation and morphogenesis. They understood morphogenesis as a closed system with living cells as the active part and biological, chemical, and physical laws as the rules. This review reports on linking mechanical aspects of developmental biology with the contemporary knowledge of tissue differentiation. We focus on the formation of cartilage (in relation to pressure), bone (in relation to shearing forces), and muscles (in relation to dilation forces). The cascade of molecules may be triggered by forces, which arise during physical cell and tissue interaction. Detailed morphological knowledge is mandatory to elucidate the exact location and timing of the regions where forces are exerted. Because this finding also holds true for the exact timing and location of signals, more 3D images of the developmental processes are required. Further research is also required to create methods for measuring forces within a tissue. The molecules whose presence and indispensability we are investigating appear to be mediators rather than creators of form. Developmental Dynamics 235:1219–1229, 2006. © 2006 Wiley-Liss, Inc.