The bidirectional communication between cells and their microenvironment is integral to both cancer progression and embryological development. This chapter illuminates major breakthroughs in our understanding of tumor cells and their microenvironment, the development of innovative experimental models that allow the study of targeting molecular signals in the tumor cell microenvironment, and finally, exploiting the convergence of embryonic and tumorigenic signaling pathways as a new therapeutic strategy for inhibiting tumor progression.